A Review of Vascular Traits and Assessment Techniques, and Their Heritability

Antonia Craig; Christian Delles; Eleanor C. Murray

doi:10.1007/s44200-022-00016-y

A Review of Vascular Traits and Assessment Techniques, and Their Heritability

Craig, Antonia; Delles, Christian; Murray, Eleanor C. 2022-06-01 00:00:00 Various tools are available to assess atherosclerosis, arterial stiffening, and endothelial function. They offer utility in the assessment of hypertensive phenotypes, in cardiovascular risk prediction, and as surrogate endpoints in clinical trials. We explore the relative influence of participant genetics, with reference to large-scale genomic studies, population-based cohorts, and candidate gene studies. We find heritability estimates highest for carotid intima-media thickness (CIMT 35–65%), followed by pulse wave velocity as a measure of arterial stiffness (26–43%), and flow mediated dilatation as a surrogate for endothelial function (14–39%); data were lacking for peripheral artery tonometry. We furthermore examine genes and polymorphisms relevant to each technique. We conclude that CIMT and pulse wave velocity dominate the existing evidence base, with fewer published genomic linkages for measures of endothelial function. We finally make recommendations regarding planning and reporting of data relating to vascular assessment techniques, particularly when genomic data are also available, to facilitate integration of these tools into cardiovascular disease research. Keywords: Heritability, Genetic, Vascular, Arterial stiffening, Endothelial, CIMT techniques and hypertensive phenotypes, including the 1 Introduction relative influence of participant sex and genetics. We Hypertension is a major risk factor for Cardiovascular Dis- explore this topic with reference to large scale genomic ease (CVD); in turn CVD is the underlying cause of more studies, population-based cohorts, and candidate gene than a quarter of deaths in the UK [1]. There are no vali - studies. dated tests that can identify early in the disease process which individuals will develop hypertension-mediated 1.1 Definitions for the Non‑expert organ damage. Dysfunctional vascular traits represent key Genome: complete set of genes in an organism includ- pathophysiological processes in the development of hyper- ing introns (non-coding sequences) and exons (coding tension and cardiovascular disease, with both inherited sequences). and reversible elements. These traits include stiffness of Genome-wide association study: entire genome surveyed the large arteries, microvascular abnormalities, endothelial for genetic variants occurring more frequently in cases dysfunction, and atherosclerosis, phenotypes often appar- than in controls. ent prior to established hypertension or organ damage. Candidate gene study: specify fewer variants of interest Hence the interest in measuring vascular function, and a priori, and aim to establish if a disease association can be in understanding the relationship between measurement confirmed. *Correspondence: Eleanor.Murray@ggc.nhs.scot.uk Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Craig et al. Artery Research (2022) 28:61–78 62 Epigenetics: genetic modification without mutations regulated by many systems (sympathetic nervous system, of the DNA sequence; occur in normal development or endocrine, and local autoregulation), each with polygenic induced by environmental factors. influences [15]. Endothelial function can be assessed using Exome: complete set of exons present in an organism ultrasound of the brachial artery with ‘flow-mediated dila - which accounts for all the coding regions of genes present. tion’ (FMD), dilation predominantly mediated by nitric SNP: single nucleotide polymorphism—DNA sequence oxide release from endothelial cells. Alternatively, periph- variations with a single nucleotide (adenine, thymine, eral arterial tonometry (PAT), commonly quantified by cytosine, or guanine) in the genome sequence altered. the Endo-PAT2000 device (Itamar Medical) also assesses Common variants: SNPs with minor allele frequency microcirculatory and endothelial function by measuring (MAF) of greater than 1%, accounting for over 90% of arterial tone or ‘hyperaemic response’ in the fingertips in genetic variation between individuals. response to proximal occlusion. EndoPAT-2000 device Mendelian Randomization: method of using measured also generates an augmentation index adjusted to a heart variation in genes of known function to examine the causal rate of 75 bpm (AI@75), similar to PWA but derived effect of a modifiable exposure on disease. from peripheral vessels. Hence, these techniques not only reflect different aspects of the pathophysiology of hyper - 2 Assessment of Vascular Function and Disease tension and cardiovascular disease but may aid identifica - Cardiovascular outcome measures in clinical trials gener- tion of different hypertensive phenotypes [16]–[18]. They ally relate to coded events such as myocardial infarction or are also well accepted as being influenced by age, BP, and death; alternatively, research trials may employ surrogate sex; factors that should be accounted for when comparing markers such as vascular stiffness and endothelial dys - techniques. Less well defined are the effects of underlying function—early functional traits known to be predictors genetic differences, i.e. the inherited component, or ‘herit - of more advanced structural changes and development of ability’ of data pertaining to techniques measuring vascu- cardiovascular disease. Assessment techniques quantify- lar health. Genotypic effects on these vascular assessment ing such traits reflect different aspects of vascular health, tools are myriad, but key checkpoints where influence may assessed in the European Society of Cardiology Working be hypothesised include vascular endothelial cell sensitiv- group position paper [2]. First, carotid ultrasound to meas- ity to extracellular stimuli, intra-cellular signalling cas- ure intima-media thickness (CIMT) has clinical utility in cades, and effects on transcription, ultimately influencing diagnosing carotid atherosclerotic vascular disease [3]–[5], production of vasoactive substances, vascular tone, and but is also linearly associated with blood pressure (BP) [6] remodelling. and adds prognostic value in the prediction of cardiovascu- lar events and mortality, see Sect. 3.1 [7, 8]. Second, pulse 3 Genetics of Hypertension wave analysis (PWA), PWA-derived augmentation index Familial and twin studies estimate that the heritable com- (AIx), and carotid-femoral pulse wave velocity (cfPWV) ponent of BP lies between 22 and 65% [19]–[22]. BP is a assess for arterial stiffness, a process characterised by func - complex trait with no single gene playing a dominant role; tional changes and structural remodelling within the arte- instead multiple genes demonstrate minor additive effects. rial wall, with associated fibrosis and calcification. These These genes encode for a variety of proteins, ion channels, measures of arterial stiffening are independent and reli - receptors, and enzymes involved in endocrine, cardiac, able predictors of hypertension, myocardial infarction and renal, vascular and neural systems that influence BP regu - stroke [9]–[11], with meta-analyses of individual patient lation. This complexity is illustrated by the heterogeneity data showing the alternative brachial-ankle PWV method of underlying pathology in the (rare) monogenic cases of also associated with cardiovascular complications [12], secondary hypertension, examples of which are discussed and stiffening of the carotid artery with incident stroke in Sect. 2.1.1. Other genes are identified only by genome [13]. The predictive strength of arterial stiffness is, how - wide association studies (GWAS); an illustrative example ever, greater in subjects with an established cardiovascular follows in Sect. 2.1.2. risk [14]. Finally, endothelial function refers to its’ ability to detect physical (shear stress) and biochemical signals, 3.1 Single Gene Disorders and respond through expression of surface molecules and Monogenic causes of hypertension are rare and mecha- production of vasoactive and inflammatory mediators. nisms varied. For example, children with homocystinuria Endothelial dysfunction precedes structural micro-circu- and familial hypercholesterolaemia develop premature latory changes. Hypertension can be both cause and con- atherosclerosis and early endothelial dysfunction [23]; in sequence of microcirculatory dysfunction, closely tied to AD glucocorticoid-remediable aldosteronism, chimeric peripheral vascular resistance, with vascular tone in turn genes encoding steroid 11ß-hydroxylase (CYP11B1) and C raig et al. Artery Research (2022) 28:61–78 63 aldosterone synthase (CYP11B2) lead to aldosterone reg- vascular techniques used to measure these hypertensive ulation by ACTH rather than angiotensin II [24, 25], salt phenotypes. and water retention, and elevation in BP [26]. Finally, AD hypertension with brachydactyly syndrome results from a 4 Carotid Intima‑Media Thickness gain of function mutation in PDE3A, encoding phospho-4.1 Heritability diesterase 3A and resulting in cerebral vascular anomalies A number of studies have reported heritability estimates and baroreceptors hypersensitivity [27]. For an in-depth for CIMT, though with disparate estimates (21 to 65%) review of monogenic hypertensive syndromes, we would despite similar adjustment for covariates, see Fig. 1 and highlight Burrello et al. [28]. Table 1 [38, 39]. Sacco et al. for example report 65% her- itability in 100 Dominican families (1390 individuals, 61% 3.2 GWAS female, mean age 46 years) after adjustment for age, sex, GWAS have identified multitudes of genetic loci associ - smoking, and BMI [39]; Cecelja et al. estimate age-adjusted ated with BP, covered in-depth elsewhere [29]. For exam- heritability at 49% (95% CI 17–63%) in 762 females of the ple ATP2B1 encoding PMCA1, a plasma membrane Twins UK cohort with mean age 58 ± 9 years [40]; whilst ATPase expressed in vascular endothelium and involved only 35% heritability is reported by Sayed-Tabatabaei et al. in calcium pumping from the cytosol to the extracellu- [41] in their assessment of 930 individuals connected in a lar compartment. GWAS can, however, be susceptible to single pedigree from an isolated population (participants false positive associations if statistical analysis lacks rigour, of the Erasmus Rucphen Family study). if the panel fails to reflect genomic variation, or the study lacks statistical power; points to remain cognizant of.4.2 Genes GWAS identifies numerous genetic loci as having possible 3.3 Epigenetics significance, and studies of candidate genes approximat - Processes of epigenetic modification include methylation, ing to these loci have also been widely reported (Table 2); post-translational histone modification, and small non- 16 of the 32 identified (50%) also have evidence of asso - coding RNAs. HSD11B2 gene promoter methylation for ciation with BP traits. Figure 2 demonstrates that many example has been associated with hypertension onset [30, genes have a role vascular remodelling, such as MMP9 31]; acetylation meanwhile promotes gene transcription of [42] encoding a gelatinase targeting type IV collagen and NOS3 (eNOS) and other genes affecting vascular tone and gelatin; CXCL12 involved in endothelial and epithelial cell salt and water homeostasis [32, 33]. Finally, small non-cod- proliferation and migration [43]; and VCAN [44] which ing RNAs (miRNA) may conversely downregulate genes encodes chondroitin sulfate proteoglycans (extracellular by binding the corresponding mRNA resulting in repres- matrix components), thus regulates cell proliferation, dif- sion of translation [33]. Population-based studies further ferentiation, and survival [45]. support the role of epigenetics in hypertension [34]. 4.3 Interactions 3.4 S ex and BP Genetics Other genes demonstrate the importance of gene-by-envi- The male–female difference in BP, vascular traits, and ronment interactions in determining CIMT, for example CVD is complex. Mediating factors include X and Y chro- MCPH1 encodes a damage response protein regulating mosome differences, sex-hormone influences, renin– cell cycle [44]. Similarly, gene–gene interactions are appar- angiotensin–aldosterone system divergence [35], societal ent, for example genes involved in cholesterol biology and and behavioral impacts, and even epigenetic differences, inflammation where high-density lipoprotein composition with females receiving genetic imprints from each parent’s is altered in an inflammatory state, with apolipoprotein- X chromosome, random X inactivation leading to fur- A-I and –A-II displaced by Serum amyloid A (SAA). SAA ther genetic heterogeneity. Gene-by-sex interactions, and SNPs rs2468844 and rs12218 alter binding affinity of SAA age (menopause)-dependent effects further complicate proteins [46, 47], with implications for reverse cholesterol interpretation. transport, CIMT, plaque formation [48], and plaque stabil- ity [49]. 3.5 Summary Bringing together the evidence of different phenotypes of 5 Vascular Stiffness: Pulse Wave Analysis and Pulse hypertension [16–18, 36, 37], determined by pathophysi- Wave Velocity ology but characterised by the aforementioned vascular 5.1 Heritability traits; and considering the exponentially increasing data Genes are estimated to account from 26 to 43% of the regarding hypertension risk alleles; it becomes impor- variability in vascular stiffness as measured by PWV (see tant to explore the genotypic and sex associations with Table 1, Fig. 1), with data derived from both population Craig et al. Artery Research (2022) 28:61–78 64 Sacco Cecelja Ge 40 Mitchell Zhao Fox Cecelja Jarr Sayed-Tabatabaei Sayed-Tabatabaei Jarr North Benjamin 0246 81012141618 CIMT es mates in orange, PWV/PWA blue, PAT no data, FMD green Fig. 1 Evidence regarding heritability of techniques assessing vascular function and twin studies [40, 41, 52, 53]. For example, the Georgia randomization data supporting causality, with genetic Cardiovascular Twin Study of 388 twins (41% black; 49% predisposition of arterial stiffness preceding hypertension male) aged 12–30 years; report 53% (42–62%) heritabil- [85]. ity for dorsalis pedis (foot) PWV [53], with no sex or race differences; additionally, the aforementioned Twins UK 5.3 Interactions cohort of 762 females, mean age 58 ± 9 report heritability Fifteen of the 24 genes (62.5%) implicated in arterial stiff - estimate of 38% (95% CI 16–63%) after adjustment, with ness have evidence of BP associations, see Table 2. Many annual progression interestingly demonstrating higher candidate gene polymorphisms studied in greater detail adjusted heritability estimates of 55% (31–64%) over relate to the renin angiotensin aldosterone system; in par- 5 years follow-up [40]. ticular angiotensin-converting enzyme (ACE) gene poly- morphisms are known to influence vascular tone, fibrosis, 5.2 Genes and ultimately arterial stiffness, though with discordant Many studies of the genetics of arterial stiffness focus on results between healthy, diabetic, and hypertensive popu- parameters other than PWV, such as pulse pressure and lations, despite adjustments for demographic and lifestyle forward and reflected wave amplitude, covered in detail factors [104, 106, 142], suggesting either an additional elsewhere [142, 143]. Looking specifically at PWV as the interaction or confounding factor is involved. Similarly, most commonly used technique, GWAS of 644 individu- the A1166C polymorphism of angiotensin II type 1 recep- als involved in the Framingham Heart Study did not find tor gene (AGTR1) was associated with arterial stiffness any variants achieving genome wide significance in the in hypertensive participants [103, 108], but not among primary analysis [91], despite the Mitchell et al.study of normotensive participants of the same study, nor the Rot- 2127 participants (mean age of 60 years, 57% female) also terdam Study population [103, 110]. Study participant derived from the Framingham cohort reporting moderate age needs to be considered in such publications as com- heritability for PWV (h = 0.40), with suggestive linkage bined effects may be apparent, e.g. C allele carriers show - regions in chromosomes 2, 7, 13, and 15 [52]. Informed by ing increased PWV, but only beyond 55 years of age [103], GWAS, and based on UK Biobank data, Zekavat et al. [85] though the Rotterdam study population was over 55 years generated a six variant polygenic arterial stiffness score, of age but still did not support the association. Addition- showing a relationship with SBP and DBP, and Mendelian ally, heterogeneous methods of estimating arterial stiffness Percent heritability C raig et al. Artery Research (2022) 28:61–78 65 Table 1 Evidence regarding heritability of techniques assessing vascular function CIMT Heritability: 35–65% BP considerations of study 65% (95% CI 60–70%): 100 Dominican families after adjustment for age, 40% had hypertension, which met inclusion criteria as a covariate for CIMT. sex, smoking, and BMI. Sacco 2009 [39] A chromosome 14q-hypertension interaction suggested for CIMT. Sacco 2009 [39] 49% (95% CI 17–63%) adjusted for age: 762 females ( Twins UK cohort), Progression of CIMT was negatively associated with treatment for hyperten- mean age 58 ± 9 years; average follow up 4.9 years; heritability of annual sion. Cecelja 2018 [40] progression of CIMT only 8% (95% CI 0–36%). Cecelja 2018 [40] 35% ± 8 (after adjustment; P < 0.001): 930 individuals connected in a Heritability 41% unadjusted, 35% adjusted for BP (and other factors), sug- single pedigree from an isolated population (Erasmus Rucphen Family gesting pleiotropic genes. Sayed-Tabatabaei 2005 [41] cohort); mean age females 51, males 54 yrs. Sayed-Tabatabaei 2005 [41] 38% ± 6 heritability, adjusted for multiple covariates; n = 906 men, 980 40% of males and 36% of females had hypertension. Estimated age- and women (mean age 57 years) from 586 extended families of the Framing- sex-adjusted heritability (c.f. the multivariable-adjusted) was 44% Fox 2003 ham Ospr ff ing cohort. Fox 2003 [50] [50] 21% ± 6 after adjustment for multiple covariates; n = 950 American Indi- Hypertension did not reach significance as a covariate for CIMT. Proportion ans of the Strong Heart Study (SHS); ≈30% with diabetes and hyperten- of variance due to covariates: 46%. North 2002 [38] sion; mean ages of different communities 41 to 44 years. North 2002 [38] 36%: 74 male twin pairs, 20 MZ, aged 42 to 69, one twin migrating to IMT correlated with S (r = 0.24, P = 0.004). Jartti 2002 [51] Sweden; IMT values also correlated between twin pairs (rMZ = 0.64, P = 0.002; rDZ = 0.46, P = 0.0006). Jartti 2002 [51] PWV and PWA Heritability: 26–43% BP considerations of study 26% ± 8 (after adjustment, P < 0.001) for PWV: n = 930; from an isolated Heritability 36% unadjusted, 26% adjusted for BP (and other factors), sug- population (Erasmus Rucphen Family); mean age females 51, males 54 yrs. gesting pleiotropic genes. Sayed-Tabatabaei 2005 [41] Sayed-Tabatabaei 2005 [41] 40% ± 9 among 1480 participants representing 817 pedigrees in the Analysed PWV separately from BP, and used additional linkage sample: the Framingham Study offspring cohort. Mean age 60 ± 10 years. Variance results mapped to separate genomic locations with credible candidate components linkage analysis identified chromosomes 2, 7, 13, and 15 for genes, suggesting distinct genetic determinants. Mitchell 2005 [52] PWV. Mitchell 2005 [52] 38% (95% CI 16–63%) adjusted: 762 females ( Twins UK cohort), mean age Demonstrate association between progression in PWV and longitudinal BP, 58 ± 9 years; average follow up 4.9 years; heritability of annual progression though not directionality. Cecelja 2018 [40] of PWV 55% (31–64%). Cecelja 2018 [40] 43% (95% CI 30–54%) / 53% (95% CI 42–62%) for radial / foot PWV respec- Overlap with genes influencing DBP. Ge 2007 [53] tively. No ethnicity or gender differences in estimates. 41% black; 49% male; aged 12–30 (mean 17.7 ± 3.3) years; n = 388, twins: 89 pairs MZ, 105 pairs DZ. Ge 2007 Georgia Cardiovascular Twin Study [53] PAT heritability: unknown BP considerations of study No published heritability estimates identified; though race, sex, and age influ- N/A ence EndoPAT results. Mulukutla 2010; Schnabel, 2011 [54, 55] FMD heritability: 14–39% BP considerations of study 14%: n = 883, 53% women; mean age 61; adjusting for stepwise model Concluded SBP is an important correlate of FMD; but not directionality or covariates, estimated heritability of brachial artery baseline diameter was whether associated through a third factor. Benjamin 2004 [56] 33 ± 7%, and FMD% was 14 ± 6%, with age-gender interaction (P = 0.01). Benjamin 2004 [56] 24%: 74 male twin pairs, 20 MZ, aged 42–69, one twin migrat- FMD correlated with SBP: r = − 0.21 (P = 0.01), and DBP: r = − 0.17 ing to Sweden; FMD did not correlate between twins, (rMZ = 0.23, (P = 0.04). Jartti 2002 [51] P = 0.34; rDZ = 0.11, P = 0.43), suggesting modest genetic component; h2 = 2 × (0.23 − 0.11) = 0.24. Jartti 2002 [51] 39% (95% CI 18–56%): 94 male twin pairs, mean age 55 ± 2.8 years; adjusted Unadjusted correlation of FMD and SBP: r = − 0.05 (P = 0.15) and DBP: for age, cholesterol, DBP, and body mass index. Zhao 2007 [57] r = − 0.08 (P = 0.08), P values corrected using generalized estimating equation. Zhao 2007 [57] CIMT carotid intima-media thickness, FMD flow-mediated dilatation, PWA pulse-wave analysis, PWV pulse-wave velocity, PAT peripheral arterial tone, BP blood pressure, MZ monozygous, DZ dizygous, N/A not applicable (no evidence of BP association) limit comparisons of studies. Mayer et al. for example find than for carotid-brachial PWV, consistent with Salvi et al. AGTR1 polymorphism significant in femoral-popliteal reporting carotid-femoral techniques are more reliable PWV but not carotid-femoral [108]; Levy et al. conversely [91, 144]. This emphasises the need for standardized tech - report greater heritability estimates for carotid-femoral nique, with the consensus now favouring carotid-femoral Craig et al. Artery Research (2022) 28:61–78 66 Table 2 Gene polymorphisms relating to techniques measuring vascular health, with consideration of sex differences and heritability estimates CIMT Candidate Genes with implicated role Design Evidence of BP association ATG10—E2-like enzyme involved in 2 ubiquitin-like modifications essen- GWAS (UK Biobank) N/A tial for autophagosome formation Strawbridge 2020 [44] RPS23—encodes a ribosomal protein Strawbridge 2020[44] GWAS (UK Biobank) N/A ATP6AP1L—ATPase H + Transporting Accessory Protein 1 Like, a protein GWAS (UK Biobank) N/A coding gene; Strawbridge 2020[44] MIR8055 and MIR4693—RNA Genes affiliated with the miRNA class; GWAS (UK Biobank) N/A Strawbridge 2020 [44] CBFA2T3—encodes a myeloid translocation gene family member which GWAS (UK Biobank) Larsson 2013 [58] interact to repress transcription; Strawbridge 2020 [44] CYP2A6 and CYP2A7- encodes a member of the cytochrome P450 GWAS (UK Biobank) Liu 2013 [59] superfamily of enzymes; Strawbridge 2020 [44] APOE E2 allele encodes a major apoprotein of the chylomicron. Natara- Meta-analysis of exome-WAS & GWAS (CHARGE) N/A jan 2016; Bis 2011; Strawbridge 2020. [44, 60, 61] BCAM—basal cell adhesion molecule; encodes Lutheran blood group Meta-analysis of GWAS (CHARGE) N/A glycoprotein, a member of the immunoglobulin superfamily and a receptor for laminin Starwbridge 2020, Bis 2011 [44, 61] ZHX2—acts as a transcriptional repressor, rs11781551 associated with Meta-analysis of GWAS (CHARGE) N/A lower CIMT; Bis 2011 [61] APOC1—expressed primarily in the liver, activated when monocytes Meta-analysis of GWAS (CHARGE) N/A differentiate into macrophages Bis 2011 [61] PINX1—Microtubule-binding protein essential for chromosome segrega- Meta-analysis of GWAS (CHARGE) Feitosa 2018 [62] tion, 1rs6601530 copy number associated with higher CIMT; Bis 2011 [61] PIK3CG—phosphorylate inositol lipids involved in immune response, Meta-analysis of GWAS (CHARGE) Carnevale 2012 [64] rs17398575 associated with 18% increased odds of plaque Bis 2011 [61], not supported by López-Mejías 2014 [63] EDNRA—encodes the receptor for endothelin-1; role in vasoconstriction; Meta-analysis of GWAS (CHARGE) Hoffman 2017 [65] rs1878406 associated with 22% increased odds of plaque; Bis 2011[61]; not supported by López-Mejías 2014 [63] ADAMTS7—a member of the ADAMTS family, a disintegrin and metal- GWAS (Dutch and Belgian Lung Cancer Screen- Warren 2017 [66], Wirtwein 2017 [68] loproteinase with thrombospondin motifs; van Setten et al., 2013 [67], ing population) not supported by López-Mejías 2014 [63] THBS2—thrombospondin 2, a disulfide-linked homotrimeric glycopro - GWAS (GeneQuest, USA) Oguri 2009 [66] tein that mediates cell-to-cell and cell-to-matrix interactions; McCarthy 2004 [69] CFDP1—protein coding gene, may play a role during embryogenesis; GWAS (IMPROVE population, European) The UK Biobank Cardio-metabolic Traits Consortium Blood Pressure Work- Gertow, 2012 [70] ing Group [66] SLC17A2—involved in phosphate transport into cells; rs17526722 associ- GWAS (RA patients) N/A ated with lower CIMT in Mexican-Americans. Arya 2018 [71] PPCDC—necessary for biosynthesis of coenzyme A; rs1867148 associ- GWAS (RA patients) Nandakumar 2019 [72] ated with lower CIMT in European-Americans; Arya 2018 [71] C raig et al. Artery Research (2022) 28:61–78 67 Table 2 (continued) CIMT Candidate Genes with implicated role Design Evidence of BP association PNPT1—RNA-binding protein involved in multiple processes e.g. import- GWAS (Erasmus Rucphen Family) Ali 2019 [74] ing RNA into mitochondria. Vojinovic 2018 [73] NOS3—nitric oxide has a role in vascular tone; Asp/Asp genotype dem- Candidate gene study Hoffman 2016 [65], Nassereddine 2018 [76], Giri [77], and others onstrated greater CIMT (P = 0.0002) Paradossi 2004 [75] SAA1 (rs12218) and SSA2 (rs2468844)—acute phase protein, associated Candidate gene study N/A with CIMT in healthy Chinese population Xie 2010[48] MMP9—involved in the breakdown of extracellular matrix; associated Candidate gene study Dhingra 2016 [78] with internal carotid but not common carotid artery IMT Armstrong 2007[42], MMP3—involved in the breakdown of extracellular matrix; relationship Candidate gene study Armstrong 2007 [42] Beilby 2005 [79] between increasing copy number and CIMT Armstrong 2007[42] TIMP3—inactivates metalloproteinases; shows relationship between Candidate gene study Armstrong 2007 [42] increasing copy number and CIMT. Armstrong 2007[42] CXCL12—arterial remodeling and thickening, rs1746048 associated with Candidate gene study Liu 2018 [80] IMT. Zabalza 2015[43] WDR12—involved in cell cycle/proliferation, signal transduction and Candidate gene study Wirtwein 2017 [68] gene regulation; inverse association with CIMT; Zabalza 2015 [43] CYBA encodes p22phox, a component of NADPH oxidase. C242T Candidate gene study N/A polymorphism was a predictor of internal CIMT following multivariable adjustment (b-coefficient − 0.119, p = 0.011). Lambrinoudaki 2018[81] GCKR—product is a regulatory protein that inhibits glucokinase in liver Candidate gene study N/A and pancreatic islet cells; rs780094 associated with carotid plaque in the American Indian but not European-, African-, or Mexican–American populations Zhang 2013[82] ADAM33—transmembrane protein, role in inflammation and regenera- Candidate gene study N/A tion; rs514174 associated with CIMT; Zhang 2019[83] TRAF1—adapter molecule that regulates the activation of NF-kappa-B Linkage analysis N/A and JNK, Heßler 2016[84] SMOC-1—glycoprotein mediating cell–matrix interactions Sacco 2009 Linkage analysis N/A [39] FBLN5—secreted protein involved in cell adhesion Sacco 2009 [39] Linkage analysis N/A CIMT Studies reporting sexspecific findings Design Evidence of BP association VCAN—female-specific locus; encodes a chondroitin sulfate proteogly- GWAS (UK Biobank) N/A can of the adventitia and intima. Strawbridge 2020 [44] MCPH1—DNA damage response protein Starwbridge 2020 [44] GWAS (UK Biobank) N/A PWV and PWA Candidate Genes with implicated role Design Evidence of BP association TEX41 (rs1006923), testis expressed 41 RNA gene. Zekavat 2019; Fung GWAS (UK BioBank) Zekavat 2019 included causal inference analyses with BP [85]. Also Warren 2019[85, 86] 2017 [66] Craig et al. Artery Research (2022) 28:61–78 68 Table 2 (continued) PWV and PWA Candidate Genes with implicated role Design Evidence of BP association FOXO1 (rs7331212)—role in T lymphocyte function and cell cycle regula- GWAS (UK BioBank) Animal model Qi 2014 [87] tion including osteogenesis and angiogenesis. Zekavat 2019, Fung 2019 [85, 86] MRVI1 (rs10840457), synonym: IRAG. Role as regulator of IP3-induced GWAS (UK BioBank) Animal model association with BP: Desch 2010 [88]; association not calcium release in platelet activation and NO-dependent smooth muscle evidenced in human studies relaxation. Fung 2019[86] COL4A1 and COL4A2 (rs3742207, rs9521719, rs872588)—type 4 collagen GWAS (UK BioBank and SardiNIA) N/A and associated with arterial stiffness (by PulseTrace PCA2); Zekavat 2019 and Fung 2019 [85, 86]; Tarasov 2009 [89] TCF20 (rs55906806): transcription factor recognises platelet-derived GWAS (UK BioBank) N/A growth factor-responsive element in MMP3 promoter. Zekavat 2019 and Fung 2019[85, 86] C1orf21 (rs1930290): chromosome 1 open reading frame. Fung 2019 [86] GWAS (UK BioBank) Evangelou 2018 [90]; Giri 2018 [77] MAGI1 (rs1495448): membrane associated guanylate kinase i.e. scaffold- GWAS (SardiNIA) Levy 2007 [91] ing protein; associated with PWV. Tarasov 2009 [89] BCL11B (rs7152623) role in immune regulation; linked to carotid-femoral Meta-analysis of 9 European ancestry GWAS Association with nocturnal dipping (GENRES (n = 204), DYNAMIC (n = 183) PWV and CVD. Mitchell 2012[92] and DILGOM cohorts (n = 180) Rimpelä 2018 [93] IL6 (pro-inflammatory cytokine). Mitchell 2005 [52](Framingham Study GWAS (Framingham) N/A offspring cohort, n = 1480) PHACTR1 (rs9349379) regulates cytoskeleton; G allele linked to decreased GWAS (UK BioBank) Gupta 2017,n = 38,817 (UK BioBank) [94] arterial stiffness (PulseTrace PCA2) Zekavat 2019[85] IGF1R (insulin-like growth factor 1 receptor) complex effects on vas- GWAS (Framingham) Schutte 2014 [95] culature including cellular proliferation, vasodilation via NO, and other endothelial functions. Mitchell 2005 [52] MEF2A (myocyte-specific enhancer factor 2A), DNA-binding transcrip - GWAS (Framingham) Evangelou 2018 [90]; Giri 2018 [77] tion factor, activates growth factor and stress-induced genes. Mitchell 2005[52] CHSY1 (chondroitin synthase 1), role in biosynthesis of chondroitin GWAS (Framingham) N/A sulfate, a glycosaminoglycan required for cell proliferation and morpho- genesis. Mitchell 2005[52] PACE4 (PCSK6) and FURIN, encodes a protease with multiple substrates GWAS (Framingham) Li 2004 [96]; Ehret 2011 [97] including pro-hormones, growth factors and von Willebrand factor; Mitchell 2005 [52] ADD2 (β-adducin), encode subunits of membrane skeletal proteins. GWAS (Framingham) N/A Mitchell 2005[52] TACR1 (tachykinin/neurokinin-1 receptor) encodes receptor for and GWAS (Framingham) N/A mediates metabolism of tachykinin substance P. Mitchell 2005[52] ADRA2B (beta adrenergic receptor) mediate catecholamine-induced inhi- GWAS (Framingham) N/A bition of adenylate cyclase through G proteins; Mitchell 2005[52] C raig et al. Artery Research (2022) 28:61–78 69 Table 2 (continued) PWV and PWA Candidate Genes with implicated role Design Evidence of BP association NOS3 rs1799983 related to central pulse pressure and forward wave Candidate gene study Hoffman 2016 [65], Nassereddine 2018 [76], Giri 2018 [77] and others amplitude parameters of PWA) in females only. Mitchell 2007[98]) TXNIP (rs7212) G allele associated with higher PWV values; functions as Candidate gene study (Brazilian cohort) N/A sensor for biomechanical and oxidative stress. Alvim 2011[99] (Brazilian cohort, n = 1518) COL1A1 polymorphisms—collagen type 1A deposition in arterial compli- Candidate gene study N/A ance. Brull 2001[100] (Young Hearts Project, UK, N = 489) ETAR (Endothelin-A and -B receptor, synonym EDNRA); endothelin being Candidate gene study Hoffman et l 2016 [65] a vasoconstrictor; gene variants influenced PWV. Lajemi 2001[101] (n = 528, untreated hypertensive Europeans) ACE I/D (rs4340)—role in BP regulation and electrolyte balance through Candidate gene studies Hoffman 2016 [65]; Sie 2009 [110], and others hydrolyzing angiotensin I, influence on arterial stiffness. Heterogeneous findings regarding implications of D allele. Mattace- Raso 2004; Benetos 1996; Dima 2008; Taniwaki 1999; Lajemi 2001; Benetos 1995; Gardier 2004; Mayer 2008[102]–[109] AGTR1 (AT II type 1 receptor)—AT II acts as a vasoconstrictor and regu- Candidate gene studies Numerous, see www. ensem bl. org; e.g. Bonnardeaux 1994 [112] lates aldosterone; positive association seen with PWV in hypertensive population. Benetos 1996, Lameji 2001; Bozec 2004; Gardier 2004; Mayer 2008. Association not supported by Sie 2009[103, 105, 107, 108, 110, 111] AGT (angiotensinogen) gene, M235T polymorphism associated with arte- Candidate gene study Hoffman 2016 [65]; Sie 2009 [110], and others rial stiffness in 98 untreated hypertensive individuals. Bozec 2004[111] PWV and PWA Studies reporting sexspecific findings Design Evidence of BP association FBN1 (Fibrillin-1) 2/3 genotype associated with higher PWA Candidate gene study Malm 2020 [114]; Medley 2002 [115] AIx and BP in females only. Malm 2020[114] (n = 315 hyperten- sive elderly subjects); Medley 2002[115] (n = 145) PAT Candidate Genes with implicated role Design Evidence of BP association CSK—cytoplasmic tyrosine kinase, role in angiotensin II-medi- GWAS (KARE) Hong 2009 [116] ated vascular smooth muscle contraction (Hong 2010)[116] NOS3 (eNOS)—produces nitric oxide which is implicated in Candidate gene study Hoffman 2016 [65], Giri 2018 [77] and others vascular smooth muscle relaxation; (Burghardt 2017)[117] APOE3/E4—a protein which is a component of lipoprotein Candidate gene study N/A (Korsakova 2018)[118] ACE—converts angiotensin I to angiotensin II, resulting in Candidate gene study Montrezol 2019 [119]; Hoffman 2016 [65]; Sie 2009 [110], and increased vasoconstrictor activity; (Korsakova 2018)[118] others SPHK 1—modulates Ang II-dependent vascular dysfunction; Animal model/human data Pietro 2020 [121] (animal and human data) (Siedlinski et at., 2017)[120] ADORA1—receptor for adenosine, activity of this receptor is Linkage analysis Evangelou 2018 [90] mediated by G proteins which inhibit adenylyl cyclase (Yoshino 2016)[122] Craig et al. Artery Research (2022) 28:61–78 70 Table 2 (continued) PAT Theorised genes, but data lacking Design Evidence of BP association SH2B3—LNK, lymphocyte-specific adaptor protein; endothelial GWAS (Global BPgen & CHARGE consortiums) Dale 2016 [125]; Newton-Cheh 2009 [123], Ference 2014 [126] cell function and vascular regeneration, though not specifi- cally reported in EndoPAT (Newton-Cheh 2009; McMaster 2014 animal model)[123, 124] PAT Studies reporting sexspecific findings Design Evidence of BP association ADORA3 strongest associations in women (member of the Linkage analysis N/A adenosine receptor group of G-protein-coupled receptors) (Yoshino 2016)[122] LPA strongest associations in women (protein encoded by this Linkage analysis Smyth 2008 [127], Wirtwein 2017 [68] gene is a serine proteinase that inhibits the activity of tissue-type plasminogen activator I) (Yoshino 2016)[122] KIF6 strongest associations in men (encodes a member of a Linkage analysis N/A family of molecular motors which are involved in intracellular transport of protein complexes) (Yoshino 2016)[122] NFKB1 strongest associations in men (a rapidly acting primary Linkage analysis N/A transcription factor found in all cell types) (Yoshino 2016)[122] FMD Candidate Genes with implicated role Design Evidence of BP association PHACTR1 (rs9349379): encoded protein binds actin and Candidate gene study Gu 2020 [128]; Zhang 2012 [129] regulates reorganization of actin cytoskeleton, also influences vascular endothelin-1 gene expression; G allele associated with decreased FMD. Gupta 2017, n = 16,662, aggregated from six cohorts[94] NOS3 ( eNOS): Glu298 → Asp polymorphism—Nitric oxide has Candidate gene study Hoffman 2016 [65], Nassereddine 2018 [76], Giri 2018 [77] and a role in vascular tone; associated with FMD Paradossi 2004, others n = 118; and Ingelsson 2008, n = 959 [75, 130] CD36 (rs3211938): integral membrane protein expressed by Candidate gene study Xueyan 2013 [132] many cell types, imports fatty acids and is a class B scavenger receptor. G allele impairs FMD after adjusting for differences in weight. Shibao 2016; 103 African American females [131] AT1R (synonym AGTR1): AT II acts as a vasoconstrictor and regu- Candidate gene study Numerous, see www. ensem bl. org; e.g. Bonnardeaux 1994 [112] lates aldosterone, hence blood volume: FMD reduced in C allele carriers Li et al. 2015, and Akpinar et al., 2014, n = 255 [133] CYBA (C242T polymorphism) encodes p22phox, a component Candidate gene study N/A of NADPH oxidase. FMD impaired in CC genotype; and T allele associated with higher FMD in hypertensive individuals. Fan et al. 2007, n = 2058; Rafiq 2014, n = 140; Lambrinoudaki 2018 n = 70 [81, 134, 135] APOE: FMD associated with E4 allele in stepwise regression Candidate gene study N/A analysis. Guangda 2003, n = 255 with diabetes [136] C raig et al. Artery Research (2022) 28:61–78 71 Table 2 (continued) FMD Candidate Genes with implicated role Design Evidence of BP association NFKB1: encoding NFKB protein, a transcription regulator; Candidate gene study N/A reduced reactive forearm blood flow identified in DD genotype; Park 2007, n = 47 PDE3A: Phosphodiesterases regulate endothelial function and Linkage analysis Associated with hypertension and brachydactyly syndrome. Maass smooth muscle contraction through role in the NO/cGMP 2015 [138]; Luft 2019 [139] pathway. Traylor 2020; ALSPAC (Avon Longitudinal Study of Parents and Children; n = 5214, integrated with MEGASTROKE: n = 60,341) [137] FMD Theorised genes, but data lacking or no association Design Evidence of BP association found SH2B3 (LNK—lymphocyte-specific adaptor protein)—endothe - GWAS (Global BPgen and CHARGE consortiums) Levy 2009 [140]; Ference 2014 [126], Hoffman 2016 [65]; Ehret lial cell function and vascular regeneration, not specifically 2016 [113] and others reported in FMD. Newton-Cheh 2009, also McMaster 2014 [123] ACE gene: mostly endothelial-bound, role in BP regulation and Candidate gene study Hoffman 2016 [65]; Sie 2009 [110], and others electrolyte balance through hydrolyzing angiotensin I; no effect on FMD. Akpinar 2014 and Celermajer 1994 [133, 141] FMD Studies reporting sexspecific findings Design Evidence of BP association Sex-specific multivariable models estimated similar effects GWAS (Global BPgen and CHARGE consortiums) Levy 2009 [140]; Ference 2014 [126], Hoffman 2016 [65]; Ehret of age on baseline artery diameter and FMD in mm for both 2016 [113] and others sexes. However,% FMD demonstrated age-gender interaction (P = 0.01), age effect being − 0.5 for men and − 0.7 for women. Benjamin 2004 [56] ACE gene: mostly endothelial-bound, role in BP regulation and N/A electrolyte balance through hydrolyzing angiotensin I; no effect on FMD. Akpinar 2014 and Celermajer 1994 [133, 141] CIMT carotid intima-media thickness, FMD flow-mediated dilatation, PWA pulse-wave analysis, PWV pulse-wave velocity, PAT peripheral arterial tone; BP, blood pressure, N/A not applicable (no evidence of BP association) Craig et al. Artery Research (2022) 28:61–78 72 CIMT Lipids CYBA MCPH1 APOE E2 ATG10 SSA1 PINX1 ADAM33 Inflammation APOC1 TRAF1 SMOC1 MMP9 PIK3CG FBLN5 MMP3 VCAN WDR12 ADAMTS7 BP BCAM TIMP3 RPS23 CFDP1 CXCL12 Remodelling ATP6AP1L CBFA2T3 PINX CYP2A6/A7 EDNRA Cell cycle MIR8055 PNPT1 NOS3 MIR4693 ZHX2 GCKR Vasoactive THBS2 SCL17A2 Other PPCDC Arterial CHSY1 Stiffness COL4A1/2 MAGI1 IL6 COL1A1 Remodelling Inflammation PHACTR1 FOXO1 FBN1 BCL11B ILGF1R ACE I AGT AGTR1 BP ADRA2B IRAG PACE4 NOS3 Endothelial Cell cycle ETAR MEF2A FURIN function TCF20 Vasoactive TEX41 C1orf21 CYBA TXNIP SH2B3 Other APOE3/E4 TACR1 NFKB1 Inflammation Lipids PHACTR1 LPA CD36 Remodelling BP ADORA1 SPHK1 ADORA3 ACE CSK AT1R NOS3 Cell cycle PDE3A Vasoactive KIF6 Other Fig. 2 Gene polymorphisms relating to techniques measuring vascular health, with genes grouped according to function. Based on data in Table 2 C raig et al. Artery Research (2022) 28:61–78 73 PWV [145]. Finally, the importance of ancestry when effect size and significant interaction with other genes and extrapolating data is highlighted by the concordance of environmental factors [151]. Further elements of the NO results derived from a common population e.g. Zekavat system implicated include PDE3A, a phosphodiesterase et al. and Fung et al. reporting UK BioBank data [85, 86], with a role in the NO/cGMP pathway. and discordant results in candidate genes and heritability Other genes have more obscure associations, such as estimates across disparate populations [52, 110]. PHACTR1 with a role in actin re-organisation but also possibly regulating vasoconstriction via endothelin-1 gene 6 Endothelial Function: Flow Mediated Dilatation expression [94]; NFKB1 encoding a protein with diverse and Peripheral Arterial Tone roles as a transcription regulator [152], and CYBA encod- 6.1 Heritability ing p22phox, a component of NADPH oxidase involved in The influence of genetics on endothelial function as meas - vascular ROS generation [134, 135], see Table 2. Yoshino ured by FMD is supported by an Italian cohort of 40 et al. studying the genetics of endothelial dysfunction healthy young people (age 6–30, 19 male) with a family report coronary vascular responses to Acetylcholine, find - history of premature myocardial infarction, demonstrat- ing 1563 SNPs connected with cardiovascular physiology ing lower FMD (5.7 ± 5.0% vs. 10.2 ± 6.6% in control sub- and pathology [122]. Variants in adenosine A1 receptor jects; P = 0.001) [146]; and by a cohort of 50 British young (ADORA 1) were associated with endothelial dysfunction people with a family history of coronary artery disease (31 in the entire cohort, while variants in adenosine A3 recep- male, mean age 25 years) also suggesting endothelial dys- tor (ADORA 3) and lipoprotein A (LPA) had the strongest function (FMD 4.9 ± 4.6% vs 8.3 ± 3.5% in control group, associations with increased risk of endothelial dysfunction P < 0.005) [147]. Among 883 participants of the Framing- in women, again highlighting that sex differences must be ham cohort (53% female; mean age 61), estimated herita- considered within this area of research. bility (accounting for covariates) of brachial artery baseline We did not find published heritability estimates regard - diameter was 0.33 ± 0.07, and FMD% was 0.14 ± 0.06; for ing the EndoPAT assessment tool of peripheral arterial FMD%, there was an age-gender interaction (P = 0.01), tone, though both race and sex are known to influence females showing steeper age-related FMD% decline [56]. results [54, 55]. Numerous candidate genes have been pro- Twin studies tend to be preferred above family studies for posed to influence vascular endothelial function, but only heritability estimation, as they allow a more precise sepa- six of them reported have specifically been linked to PAT, ration of environmental influences from genetic effects five of the six (83 percent) had commonality with BP traits. [148], including controlling for such age effects. Twin stud - see Fig. 2. The six linked to PAT include NOS3, already ies reporting FMD heritability estimates include a Finnish discussed in regard to FMD [117]; APO E, ACE [118], and cohort reporting FMD heritability of 24%, derived from 74 Sphk1 SNPs/alleles [120]. Siedlinski [120] elegantly com- male twin pairs (20 monozygous), aged 42–69 years, with bine Sphk1 identification through murine transcriptome monozygous twins demonstrating improved FMD after analysis with in vivo experiments confirming a role in migrating to Sweden (7.2 ± 4.4 vs 3.7 ± 2.9%, P = 0.003), a vasoconstriction and endothelial dysfunction, and correla- country with lower cardiovascular risk [51]. A higher esti- tion of human sphingosine-1-phosphate (S1P) serum lev- mate of 39% was reported from 94 male twin pairs from els with arterial tonometry. the USA (58 monozygous pairs), mean age 55 ± 2.8 years, 95% Caucasian [57]. 7 Heritability Study Considerations BP regulation and vascular function are complex, poly- 6.2 Genes genic traits, additionally influenced by many environ - Candidate genes linked to FMD are included in Table 2, mental factors. Molecular genetic analysis is therefore 5 of the 8 (63%) also linked to hypertension, see Fig. 2. challenging due to the sheer number of relevant genes and Examples include the Asp/Asp genotype of the endothe- their polymorphic effects, as examples in Table 2 illustrate. lial nitric oxide synthase (NOS3) Glu → Asp polymor- There are also certain limitations associated with heritabil - phism, which was associated with reduced vascular nitric ity studies, as follows. oxide (NO) generation (a potent vasodilator), decreased brachial artery FMD, and increased CIMT in a group of 7.1 Family Studies young healthy individuals free of traditional cardiovascular Classical family study design can overlook non-additive risk factors [75, 149]. NOS3 regulation involves receptor- genetic effects and shared environmental factors. Addi - mediated mechanisms (e.g. acetylcholine, bradykinin, and tionally, the underlying assumption regarding the genetic substance P) and mechanical stimuli (shear stress). How- relationship is flawed; offspring tend to inherit long seg - ever, NOS3 Asp298 is not unique; more than 100 poly- ments of DNA resulting in deviations from the expected morphisms in NOS3 have been identified [150], with small 50% DNA inheritance from each parent. Furthermore, Craig et al. Artery Research (2022) 28:61–78 74 family studies often recruit based on participant phe-8 Vascular phenotype notype, with family members then invited to partici- Various genes in Table 2 appear numerous times sug- pate. However, techniques to correct for ascertainment gesting effects on multiple vascular function assessment bias should be employed, such as Hopper and Mathews techniques. For example ACE, which cleaves angiotensin method which adjusts the heritability estimate based on I into angiotensin II with vasoconstrictive effects; ACE the mean and total variance of the genetic and environ- also stimulates the production of aldosterone, increas- mental components for each individual family grouping ing absorption of salt and water in the kidneys; ACE fur- [153]. thermore causes inactivation of the vasoactive mediator bradykinin. It is therefore not surprising that genetic poly- morphisms of ACE impact on many of the vascular assess- 7.2 Missing Heritability ment techniques described. Similarly, NOS3 (endothelial Another issue is ‘missing heritability’, i.e., the disparity nitric oxide synthase) has been identified as relevant in between heritability estimates derived from genotype data multiple assessment tools of vascular function, with local (explaining a low proportion of the variance), and from vasodilatory regulation of vascular tone and diameter (see twin studies (estimating significantly higher heritability). Table 2). Other genes or polymorphisms appear specific Missing heritability is likely a consequence of restriction to the technique or vascular trait, such as SAA1 in CIMT, of many genetic association studies to SNPs—missing COL4A in arterial stiffness (PWV), and CYBA encod- rare mutations. Gene-by-gene interactions, epigenetics, ing p22phox, a component of NADPH oxidase in FMD. and gene-by-environment interactions also contribute Some furthermore show a gene by sex interaction, such to missing heritability, through assumptions that such as VCAN locus in females, encoding a chondroitin sul- interactions are minimal, identifiable, and that variance fate proteoglycan of the adventitia and intima in CIMT explained by shared environmental factors is identical in [44], and NOS3 rs1799983 relating to central pulse pres- pairs. Such assumptions risk inflating heritability estimates sure and forward wave amplitude parameters again only by attributing the contribution of environmental factors to in females [98]. Others appear to only reach significance in genetics. those with hypertension, suggesting gene by gene or gene by environment interactions e.g. CYBA T allele associated with higher FMD only in hypertensive individuals [154]. These highlight the importance of comprehensive demo - 7.3 Directionality graphic reporting and consideration of such factors when Directionality is an inherent challenge when assessing comparing data from multiple sources. Finally, fewer stud- genotypic influences effecting vascular traits: differentiat - ies were identified reporting the genetics of measures of ing if an identified gene has a direct impact on e.g., PWV, endothelial function (FMD and PAT) compared to those or alternatively elevates BP which in turn leads to arterial relating to vascular stiffness and remodeling/atherosclero - remodeling, stiffness, and results in elevated PWV. The sis; we would propose this as an area for future study. Of high proportion of identified genetic loci and candidate note, no single gene or SNP discussed here demonstrates a genes common to both vascular phenotypes and hyperten- substantial association with the vascular traits and assess- sion outlined in Table 2 and Fig. 2 highlights this. ment techniques covered. This is to be expected in poly - genic traits, but may also reflect features of study design identified above: necessity for standardised technique with 7.4 Design these tools, underpowering and lack of external validation Most data are cross-sectional in nature, from which cohorts among many studies, gene–gene or gene– envi- change over time in vascular function or BP cannot be ronment interactions. Comparisons between different inferred. One might also hypothesize that SNPs contribut- demographic groups are also complicated if age, sex, race, ing to vascular ageing for example may influence PWV at and BP are not fully adjusted for. Researchers should be 60 years of age, but not at 30. Studies that do report her- cognizant of these in future studies. itability of baseline measures and progression, have found discrepancies [40]; therefore, duration of follow up, or population age of cross-sectional data must be reported in detail. Future studies independently confirming heritabil -9 Sex‑Differences ity of vascular traits and candidate genes, as well as their Gene-by-sex interaction may not always be captured by independence from each other and from BP are required, GWAS. Efforts to elucidate sex-specific genomic deter - and will determine the utility of vascular assessment tech- minants of BP demonstrated in 120 Canadian families niques as surrogate endpoints in trials, separate from their found that one quarter of the 539 hemodynamic, anthro- use as predictive risk tools. pometric, metabolic, and humoral traits studied were C raig et al. Artery Research (2022) 28:61–78 75 Funding both age and sex dependent, and one eighth were exclu- E. Murray received European Research Council funding to undertake an MD as sively age or sex dependent [155]. part of the Inflammatension Study (Grant number ERC-2016-COG awarded to A vascular phenotypic divide related to participant Prof T Guzik). sex may also exist, demonstrating greater discrimina- Data Availability tion between normotensive and hypertensive PWV and All data pertaining to this manuscript are already freely available and full refer- augmentation index for females than males [16] and sup- ences including DOI have been provided to facilitate access to data. ported by our own unit’s experience (unpublished). Con- versely, a collaboration establishing reference values for Declarations PWV describe apparent sex differences being almost fully Conflict of interest accounted for by age and BP differences [156]. Two points The authors have no conflicts of interest to disclose. therefore to consider if undertaking or analysing vascular Ethics Approval function data, is whether the groups were well matched or As a review of published literature, ethics approval was not required. adjustments for age and BP applied, and we suggest that researchers should also report outcome data stratified by Consent for Publication Not applicable. sex to facilitate interpretation. Received: 15 August 2021 Accepted: 26 April 2022 Published online: 1 June 2022 10 Conclusion In conclusion, CIMT, PWV/PWA, FMD and PAT offer utility as surrogate markers of atherosclerosis, arterial References 1. UK, “Office of National Statistics,” www. ons. gov. uk , 2020. stiffening, endothelial and microcirculatory function i.e. 2. C Vlachopoulos et al. The role of vascular biomarkers for primary and vascular function, and are predictive of cardiovascular secondary prevention. A position paper from the European society of risk. 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Publisher: Springer Journals
Copyright: Copyright © The Author(s) 2022
eISSN: 1876-4401
DOI: 10.1007/s44200-022-00016-y
Publisher site: See Article on Publisher Site

Abstract

Various tools are available to assess atherosclerosis, arterial stiffening, and endothelial function. They offer utility in the assessment of hypertensive phenotypes, in cardiovascular risk prediction, and as surrogate endpoints in clinical trials. We explore the relative influence of participant genetics, with reference to large-scale genomic studies, population-based cohorts, and candidate gene studies. We find heritability estimates highest for carotid intima-media thickness (CIMT 35–65%), followed by pulse wave velocity as a measure of arterial stiffness (26–43%), and flow mediated dilatation as a surrogate for endothelial function (14–39%); data were lacking for peripheral artery tonometry. We furthermore examine genes and polymorphisms relevant to each technique. We conclude that CIMT and pulse wave velocity dominate the existing evidence base, with fewer published genomic linkages for measures of endothelial function. We finally make recommendations regarding planning and reporting of data relating to vascular assessment techniques, particularly when genomic data are also available, to facilitate integration of these tools into cardiovascular disease research. Keywords: Heritability, Genetic, Vascular, Arterial stiffening, Endothelial, CIMT techniques and hypertensive phenotypes, including the 1 Introduction relative influence of participant sex and genetics. We Hypertension is a major risk factor for Cardiovascular Dis- explore this topic with reference to large scale genomic ease (CVD); in turn CVD is the underlying cause of more studies, population-based cohorts, and candidate gene than a quarter of deaths in the UK [1]. There are no vali - studies. dated tests that can identify early in the disease process which individuals will develop hypertension-mediated 1.1 Definitions for the Non‑expert organ damage. Dysfunctional vascular traits represent key Genome: complete set of genes in an organism includ- pathophysiological processes in the development of hyper- ing introns (non-coding sequences) and exons (coding tension and cardiovascular disease, with both inherited sequences). and reversible elements. These traits include stiffness of Genome-wide association study: entire genome surveyed the large arteries, microvascular abnormalities, endothelial for genetic variants occurring more frequently in cases dysfunction, and atherosclerosis, phenotypes often appar- than in controls. ent prior to established hypertension or organ damage. Candidate gene study: specify fewer variants of interest Hence the interest in measuring vascular function, and a priori, and aim to establish if a disease association can be in understanding the relationship between measurement confirmed. *Correspondence: Eleanor.Murray@ggc.nhs.scot.uk Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Craig et al. Artery Research (2022) 28:61–78 62 Epigenetics: genetic modification without mutations regulated by many systems (sympathetic nervous system, of the DNA sequence; occur in normal development or endocrine, and local autoregulation), each with polygenic induced by environmental factors. influences [15]. Endothelial function can be assessed using Exome: complete set of exons present in an organism ultrasound of the brachial artery with ‘flow-mediated dila - which accounts for all the coding regions of genes present. tion’ (FMD), dilation predominantly mediated by nitric SNP: single nucleotide polymorphism—DNA sequence oxide release from endothelial cells. Alternatively, periph- variations with a single nucleotide (adenine, thymine, eral arterial tonometry (PAT), commonly quantified by cytosine, or guanine) in the genome sequence altered. the Endo-PAT2000 device (Itamar Medical) also assesses Common variants: SNPs with minor allele frequency microcirculatory and endothelial function by measuring (MAF) of greater than 1%, accounting for over 90% of arterial tone or ‘hyperaemic response’ in the fingertips in genetic variation between individuals. response to proximal occlusion. EndoPAT-2000 device Mendelian Randomization: method of using measured also generates an augmentation index adjusted to a heart variation in genes of known function to examine the causal rate of 75 bpm (AI@75), similar to PWA but derived effect of a modifiable exposure on disease. from peripheral vessels. Hence, these techniques not only reflect different aspects of the pathophysiology of hyper - 2 Assessment of Vascular Function and Disease tension and cardiovascular disease but may aid identifica - Cardiovascular outcome measures in clinical trials gener- tion of different hypertensive phenotypes [16]–[18]. They ally relate to coded events such as myocardial infarction or are also well accepted as being influenced by age, BP, and death; alternatively, research trials may employ surrogate sex; factors that should be accounted for when comparing markers such as vascular stiffness and endothelial dys - techniques. Less well defined are the effects of underlying function—early functional traits known to be predictors genetic differences, i.e. the inherited component, or ‘herit - of more advanced structural changes and development of ability’ of data pertaining to techniques measuring vascu- cardiovascular disease. Assessment techniques quantify- lar health. Genotypic effects on these vascular assessment ing such traits reflect different aspects of vascular health, tools are myriad, but key checkpoints where influence may assessed in the European Society of Cardiology Working be hypothesised include vascular endothelial cell sensitiv- group position paper [2]. First, carotid ultrasound to meas- ity to extracellular stimuli, intra-cellular signalling cas- ure intima-media thickness (CIMT) has clinical utility in cades, and effects on transcription, ultimately influencing diagnosing carotid atherosclerotic vascular disease [3]–[5], production of vasoactive substances, vascular tone, and but is also linearly associated with blood pressure (BP) [6] remodelling. and adds prognostic value in the prediction of cardiovascu- lar events and mortality, see Sect. 3.1 [7, 8]. Second, pulse 3 Genetics of Hypertension wave analysis (PWA), PWA-derived augmentation index Familial and twin studies estimate that the heritable com- (AIx), and carotid-femoral pulse wave velocity (cfPWV) ponent of BP lies between 22 and 65% [19]–[22]. BP is a assess for arterial stiffness, a process characterised by func - complex trait with no single gene playing a dominant role; tional changes and structural remodelling within the arte- instead multiple genes demonstrate minor additive effects. rial wall, with associated fibrosis and calcification. These These genes encode for a variety of proteins, ion channels, measures of arterial stiffening are independent and reli - receptors, and enzymes involved in endocrine, cardiac, able predictors of hypertension, myocardial infarction and renal, vascular and neural systems that influence BP regu - stroke [9]–[11], with meta-analyses of individual patient lation. This complexity is illustrated by the heterogeneity data showing the alternative brachial-ankle PWV method of underlying pathology in the (rare) monogenic cases of also associated with cardiovascular complications [12], secondary hypertension, examples of which are discussed and stiffening of the carotid artery with incident stroke in Sect. 2.1.1. Other genes are identified only by genome [13]. The predictive strength of arterial stiffness is, how - wide association studies (GWAS); an illustrative example ever, greater in subjects with an established cardiovascular follows in Sect. 2.1.2. risk [14]. Finally, endothelial function refers to its’ ability to detect physical (shear stress) and biochemical signals, 3.1 Single Gene Disorders and respond through expression of surface molecules and Monogenic causes of hypertension are rare and mecha- production of vasoactive and inflammatory mediators. nisms varied. For example, children with homocystinuria Endothelial dysfunction precedes structural micro-circu- and familial hypercholesterolaemia develop premature latory changes. Hypertension can be both cause and con- atherosclerosis and early endothelial dysfunction [23]; in sequence of microcirculatory dysfunction, closely tied to AD glucocorticoid-remediable aldosteronism, chimeric peripheral vascular resistance, with vascular tone in turn genes encoding steroid 11ß-hydroxylase (CYP11B1) and C raig et al. Artery Research (2022) 28:61–78 63 aldosterone synthase (CYP11B2) lead to aldosterone reg- vascular techniques used to measure these hypertensive ulation by ACTH rather than angiotensin II [24, 25], salt phenotypes. and water retention, and elevation in BP [26]. Finally, AD hypertension with brachydactyly syndrome results from a 4 Carotid Intima‑Media Thickness gain of function mutation in PDE3A, encoding phospho-4.1 Heritability diesterase 3A and resulting in cerebral vascular anomalies A number of studies have reported heritability estimates and baroreceptors hypersensitivity [27]. For an in-depth for CIMT, though with disparate estimates (21 to 65%) review of monogenic hypertensive syndromes, we would despite similar adjustment for covariates, see Fig. 1 and highlight Burrello et al. [28]. Table 1 [38, 39]. Sacco et al. for example report 65% her- itability in 100 Dominican families (1390 individuals, 61% 3.2 GWAS female, mean age 46 years) after adjustment for age, sex, GWAS have identified multitudes of genetic loci associ - smoking, and BMI [39]; Cecelja et al. estimate age-adjusted ated with BP, covered in-depth elsewhere [29]. For exam- heritability at 49% (95% CI 17–63%) in 762 females of the ple ATP2B1 encoding PMCA1, a plasma membrane Twins UK cohort with mean age 58 ± 9 years [40]; whilst ATPase expressed in vascular endothelium and involved only 35% heritability is reported by Sayed-Tabatabaei et al. in calcium pumping from the cytosol to the extracellu- [41] in their assessment of 930 individuals connected in a lar compartment. GWAS can, however, be susceptible to single pedigree from an isolated population (participants false positive associations if statistical analysis lacks rigour, of the Erasmus Rucphen Family study). if the panel fails to reflect genomic variation, or the study lacks statistical power; points to remain cognizant of.4.2 Genes GWAS identifies numerous genetic loci as having possible 3.3 Epigenetics significance, and studies of candidate genes approximat - Processes of epigenetic modification include methylation, ing to these loci have also been widely reported (Table 2); post-translational histone modification, and small non- 16 of the 32 identified (50%) also have evidence of asso - coding RNAs. HSD11B2 gene promoter methylation for ciation with BP traits. Figure 2 demonstrates that many example has been associated with hypertension onset [30, genes have a role vascular remodelling, such as MMP9 31]; acetylation meanwhile promotes gene transcription of [42] encoding a gelatinase targeting type IV collagen and NOS3 (eNOS) and other genes affecting vascular tone and gelatin; CXCL12 involved in endothelial and epithelial cell salt and water homeostasis [32, 33]. Finally, small non-cod- proliferation and migration [43]; and VCAN [44] which ing RNAs (miRNA) may conversely downregulate genes encodes chondroitin sulfate proteoglycans (extracellular by binding the corresponding mRNA resulting in repres- matrix components), thus regulates cell proliferation, dif- sion of translation [33]. Population-based studies further ferentiation, and survival [45]. support the role of epigenetics in hypertension [34]. 4.3 Interactions 3.4 S ex and BP Genetics Other genes demonstrate the importance of gene-by-envi- The male–female difference in BP, vascular traits, and ronment interactions in determining CIMT, for example CVD is complex. Mediating factors include X and Y chro- MCPH1 encodes a damage response protein regulating mosome differences, sex-hormone influences, renin– cell cycle [44]. Similarly, gene–gene interactions are appar- angiotensin–aldosterone system divergence [35], societal ent, for example genes involved in cholesterol biology and and behavioral impacts, and even epigenetic differences, inflammation where high-density lipoprotein composition with females receiving genetic imprints from each parent’s is altered in an inflammatory state, with apolipoprotein- X chromosome, random X inactivation leading to fur- A-I and –A-II displaced by Serum amyloid A (SAA). SAA ther genetic heterogeneity. Gene-by-sex interactions, and SNPs rs2468844 and rs12218 alter binding affinity of SAA age (menopause)-dependent effects further complicate proteins [46, 47], with implications for reverse cholesterol interpretation. transport, CIMT, plaque formation [48], and plaque stabil- ity [49]. 3.5 Summary Bringing together the evidence of different phenotypes of 5 Vascular Stiffness: Pulse Wave Analysis and Pulse hypertension [16–18, 36, 37], determined by pathophysi- Wave Velocity ology but characterised by the aforementioned vascular 5.1 Heritability traits; and considering the exponentially increasing data Genes are estimated to account from 26 to 43% of the regarding hypertension risk alleles; it becomes impor- variability in vascular stiffness as measured by PWV (see tant to explore the genotypic and sex associations with Table 1, Fig. 1), with data derived from both population Craig et al. Artery Research (2022) 28:61–78 64 Sacco Cecelja Ge 40 Mitchell Zhao Fox Cecelja Jarr Sayed-Tabatabaei Sayed-Tabatabaei Jarr North Benjamin 0246 81012141618 CIMT es mates in orange, PWV/PWA blue, PAT no data, FMD green Fig. 1 Evidence regarding heritability of techniques assessing vascular function and twin studies [40, 41, 52, 53]. For example, the Georgia randomization data supporting causality, with genetic Cardiovascular Twin Study of 388 twins (41% black; 49% predisposition of arterial stiffness preceding hypertension male) aged 12–30 years; report 53% (42–62%) heritabil- [85]. ity for dorsalis pedis (foot) PWV [53], with no sex or race differences; additionally, the aforementioned Twins UK 5.3 Interactions cohort of 762 females, mean age 58 ± 9 report heritability Fifteen of the 24 genes (62.5%) implicated in arterial stiff - estimate of 38% (95% CI 16–63%) after adjustment, with ness have evidence of BP associations, see Table 2. Many annual progression interestingly demonstrating higher candidate gene polymorphisms studied in greater detail adjusted heritability estimates of 55% (31–64%) over relate to the renin angiotensin aldosterone system; in par- 5 years follow-up [40]. ticular angiotensin-converting enzyme (ACE) gene poly- morphisms are known to influence vascular tone, fibrosis, 5.2 Genes and ultimately arterial stiffness, though with discordant Many studies of the genetics of arterial stiffness focus on results between healthy, diabetic, and hypertensive popu- parameters other than PWV, such as pulse pressure and lations, despite adjustments for demographic and lifestyle forward and reflected wave amplitude, covered in detail factors [104, 106, 142], suggesting either an additional elsewhere [142, 143]. Looking specifically at PWV as the interaction or confounding factor is involved. Similarly, most commonly used technique, GWAS of 644 individu- the A1166C polymorphism of angiotensin II type 1 recep- als involved in the Framingham Heart Study did not find tor gene (AGTR1) was associated with arterial stiffness any variants achieving genome wide significance in the in hypertensive participants [103, 108], but not among primary analysis [91], despite the Mitchell et al.study of normotensive participants of the same study, nor the Rot- 2127 participants (mean age of 60 years, 57% female) also terdam Study population [103, 110]. Study participant derived from the Framingham cohort reporting moderate age needs to be considered in such publications as com- heritability for PWV (h = 0.40), with suggestive linkage bined effects may be apparent, e.g. C allele carriers show - regions in chromosomes 2, 7, 13, and 15 [52]. Informed by ing increased PWV, but only beyond 55 years of age [103], GWAS, and based on UK Biobank data, Zekavat et al. [85] though the Rotterdam study population was over 55 years generated a six variant polygenic arterial stiffness score, of age but still did not support the association. Addition- showing a relationship with SBP and DBP, and Mendelian ally, heterogeneous methods of estimating arterial stiffness Percent heritability C raig et al. Artery Research (2022) 28:61–78 65 Table 1 Evidence regarding heritability of techniques assessing vascular function CIMT Heritability: 35–65% BP considerations of study 65% (95% CI 60–70%): 100 Dominican families after adjustment for age, 40% had hypertension, which met inclusion criteria as a covariate for CIMT. sex, smoking, and BMI. Sacco 2009 [39] A chromosome 14q-hypertension interaction suggested for CIMT. Sacco 2009 [39] 49% (95% CI 17–63%) adjusted for age: 762 females ( Twins UK cohort), Progression of CIMT was negatively associated with treatment for hyperten- mean age 58 ± 9 years; average follow up 4.9 years; heritability of annual sion. Cecelja 2018 [40] progression of CIMT only 8% (95% CI 0–36%). Cecelja 2018 [40] 35% ± 8 (after adjustment; P < 0.001): 930 individuals connected in a Heritability 41% unadjusted, 35% adjusted for BP (and other factors), sug- single pedigree from an isolated population (Erasmus Rucphen Family gesting pleiotropic genes. Sayed-Tabatabaei 2005 [41] cohort); mean age females 51, males 54 yrs. Sayed-Tabatabaei 2005 [41] 38% ± 6 heritability, adjusted for multiple covariates; n = 906 men, 980 40% of males and 36% of females had hypertension. Estimated age- and women (mean age 57 years) from 586 extended families of the Framing- sex-adjusted heritability (c.f. the multivariable-adjusted) was 44% Fox 2003 ham Ospr ff ing cohort. Fox 2003 [50] [50] 21% ± 6 after adjustment for multiple covariates; n = 950 American Indi- Hypertension did not reach significance as a covariate for CIMT. Proportion ans of the Strong Heart Study (SHS); ≈30% with diabetes and hyperten- of variance due to covariates: 46%. North 2002 [38] sion; mean ages of different communities 41 to 44 years. North 2002 [38] 36%: 74 male twin pairs, 20 MZ, aged 42 to 69, one twin migrating to IMT correlated with S (r = 0.24, P = 0.004). Jartti 2002 [51] Sweden; IMT values also correlated between twin pairs (rMZ = 0.64, P = 0.002; rDZ = 0.46, P = 0.0006). Jartti 2002 [51] PWV and PWA Heritability: 26–43% BP considerations of study 26% ± 8 (after adjustment, P < 0.001) for PWV: n = 930; from an isolated Heritability 36% unadjusted, 26% adjusted for BP (and other factors), sug- population (Erasmus Rucphen Family); mean age females 51, males 54 yrs. gesting pleiotropic genes. Sayed-Tabatabaei 2005 [41] Sayed-Tabatabaei 2005 [41] 40% ± 9 among 1480 participants representing 817 pedigrees in the Analysed PWV separately from BP, and used additional linkage sample: the Framingham Study offspring cohort. Mean age 60 ± 10 years. Variance results mapped to separate genomic locations with credible candidate components linkage analysis identified chromosomes 2, 7, 13, and 15 for genes, suggesting distinct genetic determinants. Mitchell 2005 [52] PWV. Mitchell 2005 [52] 38% (95% CI 16–63%) adjusted: 762 females ( Twins UK cohort), mean age Demonstrate association between progression in PWV and longitudinal BP, 58 ± 9 years; average follow up 4.9 years; heritability of annual progression though not directionality. Cecelja 2018 [40] of PWV 55% (31–64%). Cecelja 2018 [40] 43% (95% CI 30–54%) / 53% (95% CI 42–62%) for radial / foot PWV respec- Overlap with genes influencing DBP. Ge 2007 [53] tively. No ethnicity or gender differences in estimates. 41% black; 49% male; aged 12–30 (mean 17.7 ± 3.3) years; n = 388, twins: 89 pairs MZ, 105 pairs DZ. Ge 2007 Georgia Cardiovascular Twin Study [53] PAT heritability: unknown BP considerations of study No published heritability estimates identified; though race, sex, and age influ- N/A ence EndoPAT results. Mulukutla 2010; Schnabel, 2011 [54, 55] FMD heritability: 14–39% BP considerations of study 14%: n = 883, 53% women; mean age 61; adjusting for stepwise model Concluded SBP is an important correlate of FMD; but not directionality or covariates, estimated heritability of brachial artery baseline diameter was whether associated through a third factor. Benjamin 2004 [56] 33 ± 7%, and FMD% was 14 ± 6%, with age-gender interaction (P = 0.01). Benjamin 2004 [56] 24%: 74 male twin pairs, 20 MZ, aged 42–69, one twin migrat- FMD correlated with SBP: r = − 0.21 (P = 0.01), and DBP: r = − 0.17 ing to Sweden; FMD did not correlate between twins, (rMZ = 0.23, (P = 0.04). Jartti 2002 [51] P = 0.34; rDZ = 0.11, P = 0.43), suggesting modest genetic component; h2 = 2 × (0.23 − 0.11) = 0.24. Jartti 2002 [51] 39% (95% CI 18–56%): 94 male twin pairs, mean age 55 ± 2.8 years; adjusted Unadjusted correlation of FMD and SBP: r = − 0.05 (P = 0.15) and DBP: for age, cholesterol, DBP, and body mass index. Zhao 2007 [57] r = − 0.08 (P = 0.08), P values corrected using generalized estimating equation. Zhao 2007 [57] CIMT carotid intima-media thickness, FMD flow-mediated dilatation, PWA pulse-wave analysis, PWV pulse-wave velocity, PAT peripheral arterial tone, BP blood pressure, MZ monozygous, DZ dizygous, N/A not applicable (no evidence of BP association) limit comparisons of studies. Mayer et al. for example find than for carotid-brachial PWV, consistent with Salvi et al. AGTR1 polymorphism significant in femoral-popliteal reporting carotid-femoral techniques are more reliable PWV but not carotid-femoral [108]; Levy et al. conversely [91, 144]. This emphasises the need for standardized tech - report greater heritability estimates for carotid-femoral nique, with the consensus now favouring carotid-femoral Craig et al. Artery Research (2022) 28:61–78 66 Table 2 Gene polymorphisms relating to techniques measuring vascular health, with consideration of sex differences and heritability estimates CIMT Candidate Genes with implicated role Design Evidence of BP association ATG10—E2-like enzyme involved in 2 ubiquitin-like modifications essen- GWAS (UK Biobank) N/A tial for autophagosome formation Strawbridge 2020 [44] RPS23—encodes a ribosomal protein Strawbridge 2020[44] GWAS (UK Biobank) N/A ATP6AP1L—ATPase H + Transporting Accessory Protein 1 Like, a protein GWAS (UK Biobank) N/A coding gene; Strawbridge 2020[44] MIR8055 and MIR4693—RNA Genes affiliated with the miRNA class; GWAS (UK Biobank) N/A Strawbridge 2020 [44] CBFA2T3—encodes a myeloid translocation gene family member which GWAS (UK Biobank) Larsson 2013 [58] interact to repress transcription; Strawbridge 2020 [44] CYP2A6 and CYP2A7- encodes a member of the cytochrome P450 GWAS (UK Biobank) Liu 2013 [59] superfamily of enzymes; Strawbridge 2020 [44] APOE E2 allele encodes a major apoprotein of the chylomicron. Natara- Meta-analysis of exome-WAS & GWAS (CHARGE) N/A jan 2016; Bis 2011; Strawbridge 2020. [44, 60, 61] BCAM—basal cell adhesion molecule; encodes Lutheran blood group Meta-analysis of GWAS (CHARGE) N/A glycoprotein, a member of the immunoglobulin superfamily and a receptor for laminin Starwbridge 2020, Bis 2011 [44, 61] ZHX2—acts as a transcriptional repressor, rs11781551 associated with Meta-analysis of GWAS (CHARGE) N/A lower CIMT; Bis 2011 [61] APOC1—expressed primarily in the liver, activated when monocytes Meta-analysis of GWAS (CHARGE) N/A differentiate into macrophages Bis 2011 [61] PINX1—Microtubule-binding protein essential for chromosome segrega- Meta-analysis of GWAS (CHARGE) Feitosa 2018 [62] tion, 1rs6601530 copy number associated with higher CIMT; Bis 2011 [61] PIK3CG—phosphorylate inositol lipids involved in immune response, Meta-analysis of GWAS (CHARGE) Carnevale 2012 [64] rs17398575 associated with 18% increased odds of plaque Bis 2011 [61], not supported by López-Mejías 2014 [63] EDNRA—encodes the receptor for endothelin-1; role in vasoconstriction; Meta-analysis of GWAS (CHARGE) Hoffman 2017 [65] rs1878406 associated with 22% increased odds of plaque; Bis 2011[61]; not supported by López-Mejías 2014 [63] ADAMTS7—a member of the ADAMTS family, a disintegrin and metal- GWAS (Dutch and Belgian Lung Cancer Screen- Warren 2017 [66], Wirtwein 2017 [68] loproteinase with thrombospondin motifs; van Setten et al., 2013 [67], ing population) not supported by López-Mejías 2014 [63] THBS2—thrombospondin 2, a disulfide-linked homotrimeric glycopro - GWAS (GeneQuest, USA) Oguri 2009 [66] tein that mediates cell-to-cell and cell-to-matrix interactions; McCarthy 2004 [69] CFDP1—protein coding gene, may play a role during embryogenesis; GWAS (IMPROVE population, European) The UK Biobank Cardio-metabolic Traits Consortium Blood Pressure Work- Gertow, 2012 [70] ing Group [66] SLC17A2—involved in phosphate transport into cells; rs17526722 associ- GWAS (RA patients) N/A ated with lower CIMT in Mexican-Americans. Arya 2018 [71] PPCDC—necessary for biosynthesis of coenzyme A; rs1867148 associ- GWAS (RA patients) Nandakumar 2019 [72] ated with lower CIMT in European-Americans; Arya 2018 [71] C raig et al. Artery Research (2022) 28:61–78 67 Table 2 (continued) CIMT Candidate Genes with implicated role Design Evidence of BP association PNPT1—RNA-binding protein involved in multiple processes e.g. import- GWAS (Erasmus Rucphen Family) Ali 2019 [74] ing RNA into mitochondria. Vojinovic 2018 [73] NOS3—nitric oxide has a role in vascular tone; Asp/Asp genotype dem- Candidate gene study Hoffman 2016 [65], Nassereddine 2018 [76], Giri [77], and others onstrated greater CIMT (P = 0.0002) Paradossi 2004 [75] SAA1 (rs12218) and SSA2 (rs2468844)—acute phase protein, associated Candidate gene study N/A with CIMT in healthy Chinese population Xie 2010[48] MMP9—involved in the breakdown of extracellular matrix; associated Candidate gene study Dhingra 2016 [78] with internal carotid but not common carotid artery IMT Armstrong 2007[42], MMP3—involved in the breakdown of extracellular matrix; relationship Candidate gene study Armstrong 2007 [42] Beilby 2005 [79] between increasing copy number and CIMT Armstrong 2007[42] TIMP3—inactivates metalloproteinases; shows relationship between Candidate gene study Armstrong 2007 [42] increasing copy number and CIMT. Armstrong 2007[42] CXCL12—arterial remodeling and thickening, rs1746048 associated with Candidate gene study Liu 2018 [80] IMT. Zabalza 2015[43] WDR12—involved in cell cycle/proliferation, signal transduction and Candidate gene study Wirtwein 2017 [68] gene regulation; inverse association with CIMT; Zabalza 2015 [43] CYBA encodes p22phox, a component of NADPH oxidase. C242T Candidate gene study N/A polymorphism was a predictor of internal CIMT following multivariable adjustment (b-coefficient − 0.119, p = 0.011). Lambrinoudaki 2018[81] GCKR—product is a regulatory protein that inhibits glucokinase in liver Candidate gene study N/A and pancreatic islet cells; rs780094 associated with carotid plaque in the American Indian but not European-, African-, or Mexican–American populations Zhang 2013[82] ADAM33—transmembrane protein, role in inflammation and regenera- Candidate gene study N/A tion; rs514174 associated with CIMT; Zhang 2019[83] TRAF1—adapter molecule that regulates the activation of NF-kappa-B Linkage analysis N/A and JNK, Heßler 2016[84] SMOC-1—glycoprotein mediating cell–matrix interactions Sacco 2009 Linkage analysis N/A [39] FBLN5—secreted protein involved in cell adhesion Sacco 2009 [39] Linkage analysis N/A CIMT Studies reporting sexspecific findings Design Evidence of BP association VCAN—female-specific locus; encodes a chondroitin sulfate proteogly- GWAS (UK Biobank) N/A can of the adventitia and intima. Strawbridge 2020 [44] MCPH1—DNA damage response protein Starwbridge 2020 [44] GWAS (UK Biobank) N/A PWV and PWA Candidate Genes with implicated role Design Evidence of BP association TEX41 (rs1006923), testis expressed 41 RNA gene. Zekavat 2019; Fung GWAS (UK BioBank) Zekavat 2019 included causal inference analyses with BP [85]. Also Warren 2019[85, 86] 2017 [66] Craig et al. Artery Research (2022) 28:61–78 68 Table 2 (continued) PWV and PWA Candidate Genes with implicated role Design Evidence of BP association FOXO1 (rs7331212)—role in T lymphocyte function and cell cycle regula- GWAS (UK BioBank) Animal model Qi 2014 [87] tion including osteogenesis and angiogenesis. Zekavat 2019, Fung 2019 [85, 86] MRVI1 (rs10840457), synonym: IRAG. Role as regulator of IP3-induced GWAS (UK BioBank) Animal model association with BP: Desch 2010 [88]; association not calcium release in platelet activation and NO-dependent smooth muscle evidenced in human studies relaxation. Fung 2019[86] COL4A1 and COL4A2 (rs3742207, rs9521719, rs872588)—type 4 collagen GWAS (UK BioBank and SardiNIA) N/A and associated with arterial stiffness (by PulseTrace PCA2); Zekavat 2019 and Fung 2019 [85, 86]; Tarasov 2009 [89] TCF20 (rs55906806): transcription factor recognises platelet-derived GWAS (UK BioBank) N/A growth factor-responsive element in MMP3 promoter. Zekavat 2019 and Fung 2019[85, 86] C1orf21 (rs1930290): chromosome 1 open reading frame. Fung 2019 [86] GWAS (UK BioBank) Evangelou 2018 [90]; Giri 2018 [77] MAGI1 (rs1495448): membrane associated guanylate kinase i.e. scaffold- GWAS (SardiNIA) Levy 2007 [91] ing protein; associated with PWV. Tarasov 2009 [89] BCL11B (rs7152623) role in immune regulation; linked to carotid-femoral Meta-analysis of 9 European ancestry GWAS Association with nocturnal dipping (GENRES (n = 204), DYNAMIC (n = 183) PWV and CVD. Mitchell 2012[92] and DILGOM cohorts (n = 180) Rimpelä 2018 [93] IL6 (pro-inflammatory cytokine). Mitchell 2005 [52](Framingham Study GWAS (Framingham) N/A offspring cohort, n = 1480) PHACTR1 (rs9349379) regulates cytoskeleton; G allele linked to decreased GWAS (UK BioBank) Gupta 2017,n = 38,817 (UK BioBank) [94] arterial stiffness (PulseTrace PCA2) Zekavat 2019[85] IGF1R (insulin-like growth factor 1 receptor) complex effects on vas- GWAS (Framingham) Schutte 2014 [95] culature including cellular proliferation, vasodilation via NO, and other endothelial functions. Mitchell 2005 [52] MEF2A (myocyte-specific enhancer factor 2A), DNA-binding transcrip - GWAS (Framingham) Evangelou 2018 [90]; Giri 2018 [77] tion factor, activates growth factor and stress-induced genes. Mitchell 2005[52] CHSY1 (chondroitin synthase 1), role in biosynthesis of chondroitin GWAS (Framingham) N/A sulfate, a glycosaminoglycan required for cell proliferation and morpho- genesis. Mitchell 2005[52] PACE4 (PCSK6) and FURIN, encodes a protease with multiple substrates GWAS (Framingham) Li 2004 [96]; Ehret 2011 [97] including pro-hormones, growth factors and von Willebrand factor; Mitchell 2005 [52] ADD2 (β-adducin), encode subunits of membrane skeletal proteins. GWAS (Framingham) N/A Mitchell 2005[52] TACR1 (tachykinin/neurokinin-1 receptor) encodes receptor for and GWAS (Framingham) N/A mediates metabolism of tachykinin substance P. Mitchell 2005[52] ADRA2B (beta adrenergic receptor) mediate catecholamine-induced inhi- GWAS (Framingham) N/A bition of adenylate cyclase through G proteins; Mitchell 2005[52] C raig et al. Artery Research (2022) 28:61–78 69 Table 2 (continued) PWV and PWA Candidate Genes with implicated role Design Evidence of BP association NOS3 rs1799983 related to central pulse pressure and forward wave Candidate gene study Hoffman 2016 [65], Nassereddine 2018 [76], Giri 2018 [77] and others amplitude parameters of PWA) in females only. Mitchell 2007[98]) TXNIP (rs7212) G allele associated with higher PWV values; functions as Candidate gene study (Brazilian cohort) N/A sensor for biomechanical and oxidative stress. Alvim 2011[99] (Brazilian cohort, n = 1518) COL1A1 polymorphisms—collagen type 1A deposition in arterial compli- Candidate gene study N/A ance. Brull 2001[100] (Young Hearts Project, UK, N = 489) ETAR (Endothelin-A and -B receptor, synonym EDNRA); endothelin being Candidate gene study Hoffman et l 2016 [65] a vasoconstrictor; gene variants influenced PWV. Lajemi 2001[101] (n = 528, untreated hypertensive Europeans) ACE I/D (rs4340)—role in BP regulation and electrolyte balance through Candidate gene studies Hoffman 2016 [65]; Sie 2009 [110], and others hydrolyzing angiotensin I, influence on arterial stiffness. Heterogeneous findings regarding implications of D allele. Mattace- Raso 2004; Benetos 1996; Dima 2008; Taniwaki 1999; Lajemi 2001; Benetos 1995; Gardier 2004; Mayer 2008[102]–[109] AGTR1 (AT II type 1 receptor)—AT II acts as a vasoconstrictor and regu- Candidate gene studies Numerous, see www. ensem bl. org; e.g. Bonnardeaux 1994 [112] lates aldosterone; positive association seen with PWV in hypertensive population. Benetos 1996, Lameji 2001; Bozec 2004; Gardier 2004; Mayer 2008. Association not supported by Sie 2009[103, 105, 107, 108, 110, 111] AGT (angiotensinogen) gene, M235T polymorphism associated with arte- Candidate gene study Hoffman 2016 [65]; Sie 2009 [110], and others rial stiffness in 98 untreated hypertensive individuals. Bozec 2004[111] PWV and PWA Studies reporting sexspecific findings Design Evidence of BP association FBN1 (Fibrillin-1) 2/3 genotype associated with higher PWA Candidate gene study Malm 2020 [114]; Medley 2002 [115] AIx and BP in females only. Malm 2020[114] (n = 315 hyperten- sive elderly subjects); Medley 2002[115] (n = 145) PAT Candidate Genes with implicated role Design Evidence of BP association CSK—cytoplasmic tyrosine kinase, role in angiotensin II-medi- GWAS (KARE) Hong 2009 [116] ated vascular smooth muscle contraction (Hong 2010)[116] NOS3 (eNOS)—produces nitric oxide which is implicated in Candidate gene study Hoffman 2016 [65], Giri 2018 [77] and others vascular smooth muscle relaxation; (Burghardt 2017)[117] APOE3/E4—a protein which is a component of lipoprotein Candidate gene study N/A (Korsakova 2018)[118] ACE—converts angiotensin I to angiotensin II, resulting in Candidate gene study Montrezol 2019 [119]; Hoffman 2016 [65]; Sie 2009 [110], and increased vasoconstrictor activity; (Korsakova 2018)[118] others SPHK 1—modulates Ang II-dependent vascular dysfunction; Animal model/human data Pietro 2020 [121] (animal and human data) (Siedlinski et at., 2017)[120] ADORA1—receptor for adenosine, activity of this receptor is Linkage analysis Evangelou 2018 [90] mediated by G proteins which inhibit adenylyl cyclase (Yoshino 2016)[122] Craig et al. Artery Research (2022) 28:61–78 70 Table 2 (continued) PAT Theorised genes, but data lacking Design Evidence of BP association SH2B3—LNK, lymphocyte-specific adaptor protein; endothelial GWAS (Global BPgen & CHARGE consortiums) Dale 2016 [125]; Newton-Cheh 2009 [123], Ference 2014 [126] cell function and vascular regeneration, though not specifi- cally reported in EndoPAT (Newton-Cheh 2009; McMaster 2014 animal model)[123, 124] PAT Studies reporting sexspecific findings Design Evidence of BP association ADORA3 strongest associations in women (member of the Linkage analysis N/A adenosine receptor group of G-protein-coupled receptors) (Yoshino 2016)[122] LPA strongest associations in women (protein encoded by this Linkage analysis Smyth 2008 [127], Wirtwein 2017 [68] gene is a serine proteinase that inhibits the activity of tissue-type plasminogen activator I) (Yoshino 2016)[122] KIF6 strongest associations in men (encodes a member of a Linkage analysis N/A family of molecular motors which are involved in intracellular transport of protein complexes) (Yoshino 2016)[122] NFKB1 strongest associations in men (a rapidly acting primary Linkage analysis N/A transcription factor found in all cell types) (Yoshino 2016)[122] FMD Candidate Genes with implicated role Design Evidence of BP association PHACTR1 (rs9349379): encoded protein binds actin and Candidate gene study Gu 2020 [128]; Zhang 2012 [129] regulates reorganization of actin cytoskeleton, also influences vascular endothelin-1 gene expression; G allele associated with decreased FMD. Gupta 2017, n = 16,662, aggregated from six cohorts[94] NOS3 ( eNOS): Glu298 → Asp polymorphism—Nitric oxide has Candidate gene study Hoffman 2016 [65], Nassereddine 2018 [76], Giri 2018 [77] and a role in vascular tone; associated with FMD Paradossi 2004, others n = 118; and Ingelsson 2008, n = 959 [75, 130] CD36 (rs3211938): integral membrane protein expressed by Candidate gene study Xueyan 2013 [132] many cell types, imports fatty acids and is a class B scavenger receptor. G allele impairs FMD after adjusting for differences in weight. Shibao 2016; 103 African American females [131] AT1R (synonym AGTR1): AT II acts as a vasoconstrictor and regu- Candidate gene study Numerous, see www. ensem bl. org; e.g. Bonnardeaux 1994 [112] lates aldosterone, hence blood volume: FMD reduced in C allele carriers Li et al. 2015, and Akpinar et al., 2014, n = 255 [133] CYBA (C242T polymorphism) encodes p22phox, a component Candidate gene study N/A of NADPH oxidase. FMD impaired in CC genotype; and T allele associated with higher FMD in hypertensive individuals. Fan et al. 2007, n = 2058; Rafiq 2014, n = 140; Lambrinoudaki 2018 n = 70 [81, 134, 135] APOE: FMD associated with E4 allele in stepwise regression Candidate gene study N/A analysis. Guangda 2003, n = 255 with diabetes [136] C raig et al. Artery Research (2022) 28:61–78 71 Table 2 (continued) FMD Candidate Genes with implicated role Design Evidence of BP association NFKB1: encoding NFKB protein, a transcription regulator; Candidate gene study N/A reduced reactive forearm blood flow identified in DD genotype; Park 2007, n = 47 PDE3A: Phosphodiesterases regulate endothelial function and Linkage analysis Associated with hypertension and brachydactyly syndrome. Maass smooth muscle contraction through role in the NO/cGMP 2015 [138]; Luft 2019 [139] pathway. Traylor 2020; ALSPAC (Avon Longitudinal Study of Parents and Children; n = 5214, integrated with MEGASTROKE: n = 60,341) [137] FMD Theorised genes, but data lacking or no association Design Evidence of BP association found SH2B3 (LNK—lymphocyte-specific adaptor protein)—endothe - GWAS (Global BPgen and CHARGE consortiums) Levy 2009 [140]; Ference 2014 [126], Hoffman 2016 [65]; Ehret lial cell function and vascular regeneration, not specifically 2016 [113] and others reported in FMD. Newton-Cheh 2009, also McMaster 2014 [123] ACE gene: mostly endothelial-bound, role in BP regulation and Candidate gene study Hoffman 2016 [65]; Sie 2009 [110], and others electrolyte balance through hydrolyzing angiotensin I; no effect on FMD. Akpinar 2014 and Celermajer 1994 [133, 141] FMD Studies reporting sexspecific findings Design Evidence of BP association Sex-specific multivariable models estimated similar effects GWAS (Global BPgen and CHARGE consortiums) Levy 2009 [140]; Ference 2014 [126], Hoffman 2016 [65]; Ehret of age on baseline artery diameter and FMD in mm for both 2016 [113] and others sexes. However,% FMD demonstrated age-gender interaction (P = 0.01), age effect being − 0.5 for men and − 0.7 for women. Benjamin 2004 [56] ACE gene: mostly endothelial-bound, role in BP regulation and N/A electrolyte balance through hydrolyzing angiotensin I; no effect on FMD. Akpinar 2014 and Celermajer 1994 [133, 141] CIMT carotid intima-media thickness, FMD flow-mediated dilatation, PWA pulse-wave analysis, PWV pulse-wave velocity, PAT peripheral arterial tone; BP, blood pressure, N/A not applicable (no evidence of BP association) Craig et al. Artery Research (2022) 28:61–78 72 CIMT Lipids CYBA MCPH1 APOE E2 ATG10 SSA1 PINX1 ADAM33 Inflammation APOC1 TRAF1 SMOC1 MMP9 PIK3CG FBLN5 MMP3 VCAN WDR12 ADAMTS7 BP BCAM TIMP3 RPS23 CFDP1 CXCL12 Remodelling ATP6AP1L CBFA2T3 PINX CYP2A6/A7 EDNRA Cell cycle MIR8055 PNPT1 NOS3 MIR4693 ZHX2 GCKR Vasoactive THBS2 SCL17A2 Other PPCDC Arterial CHSY1 Stiffness COL4A1/2 MAGI1 IL6 COL1A1 Remodelling Inflammation PHACTR1 FOXO1 FBN1 BCL11B ILGF1R ACE I AGT AGTR1 BP ADRA2B IRAG PACE4 NOS3 Endothelial Cell cycle ETAR MEF2A FURIN function TCF20 Vasoactive TEX41 C1orf21 CYBA TXNIP SH2B3 Other APOE3/E4 TACR1 NFKB1 Inflammation Lipids PHACTR1 LPA CD36 Remodelling BP ADORA1 SPHK1 ADORA3 ACE CSK AT1R NOS3 Cell cycle PDE3A Vasoactive KIF6 Other Fig. 2 Gene polymorphisms relating to techniques measuring vascular health, with genes grouped according to function. Based on data in Table 2 C raig et al. Artery Research (2022) 28:61–78 73 PWV [145]. Finally, the importance of ancestry when effect size and significant interaction with other genes and extrapolating data is highlighted by the concordance of environmental factors [151]. Further elements of the NO results derived from a common population e.g. Zekavat system implicated include PDE3A, a phosphodiesterase et al. and Fung et al. reporting UK BioBank data [85, 86], with a role in the NO/cGMP pathway. and discordant results in candidate genes and heritability Other genes have more obscure associations, such as estimates across disparate populations [52, 110]. PHACTR1 with a role in actin re-organisation but also possibly regulating vasoconstriction via endothelin-1 gene 6 Endothelial Function: Flow Mediated Dilatation expression [94]; NFKB1 encoding a protein with diverse and Peripheral Arterial Tone roles as a transcription regulator [152], and CYBA encod- 6.1 Heritability ing p22phox, a component of NADPH oxidase involved in The influence of genetics on endothelial function as meas - vascular ROS generation [134, 135], see Table 2. Yoshino ured by FMD is supported by an Italian cohort of 40 et al. studying the genetics of endothelial dysfunction healthy young people (age 6–30, 19 male) with a family report coronary vascular responses to Acetylcholine, find - history of premature myocardial infarction, demonstrat- ing 1563 SNPs connected with cardiovascular physiology ing lower FMD (5.7 ± 5.0% vs. 10.2 ± 6.6% in control sub- and pathology [122]. Variants in adenosine A1 receptor jects; P = 0.001) [146]; and by a cohort of 50 British young (ADORA 1) were associated with endothelial dysfunction people with a family history of coronary artery disease (31 in the entire cohort, while variants in adenosine A3 recep- male, mean age 25 years) also suggesting endothelial dys- tor (ADORA 3) and lipoprotein A (LPA) had the strongest function (FMD 4.9 ± 4.6% vs 8.3 ± 3.5% in control group, associations with increased risk of endothelial dysfunction P < 0.005) [147]. Among 883 participants of the Framing- in women, again highlighting that sex differences must be ham cohort (53% female; mean age 61), estimated herita- considered within this area of research. bility (accounting for covariates) of brachial artery baseline We did not find published heritability estimates regard - diameter was 0.33 ± 0.07, and FMD% was 0.14 ± 0.06; for ing the EndoPAT assessment tool of peripheral arterial FMD%, there was an age-gender interaction (P = 0.01), tone, though both race and sex are known to influence females showing steeper age-related FMD% decline [56]. results [54, 55]. Numerous candidate genes have been pro- Twin studies tend to be preferred above family studies for posed to influence vascular endothelial function, but only heritability estimation, as they allow a more precise sepa- six of them reported have specifically been linked to PAT, ration of environmental influences from genetic effects five of the six (83 percent) had commonality with BP traits. [148], including controlling for such age effects. Twin stud - see Fig. 2. The six linked to PAT include NOS3, already ies reporting FMD heritability estimates include a Finnish discussed in regard to FMD [117]; APO E, ACE [118], and cohort reporting FMD heritability of 24%, derived from 74 Sphk1 SNPs/alleles [120]. Siedlinski [120] elegantly com- male twin pairs (20 monozygous), aged 42–69 years, with bine Sphk1 identification through murine transcriptome monozygous twins demonstrating improved FMD after analysis with in vivo experiments confirming a role in migrating to Sweden (7.2 ± 4.4 vs 3.7 ± 2.9%, P = 0.003), a vasoconstriction and endothelial dysfunction, and correla- country with lower cardiovascular risk [51]. A higher esti- tion of human sphingosine-1-phosphate (S1P) serum lev- mate of 39% was reported from 94 male twin pairs from els with arterial tonometry. the USA (58 monozygous pairs), mean age 55 ± 2.8 years, 95% Caucasian [57]. 7 Heritability Study Considerations BP regulation and vascular function are complex, poly- 6.2 Genes genic traits, additionally influenced by many environ - Candidate genes linked to FMD are included in Table 2, mental factors. Molecular genetic analysis is therefore 5 of the 8 (63%) also linked to hypertension, see Fig. 2. challenging due to the sheer number of relevant genes and Examples include the Asp/Asp genotype of the endothe- their polymorphic effects, as examples in Table 2 illustrate. lial nitric oxide synthase (NOS3) Glu → Asp polymor- There are also certain limitations associated with heritabil - phism, which was associated with reduced vascular nitric ity studies, as follows. oxide (NO) generation (a potent vasodilator), decreased brachial artery FMD, and increased CIMT in a group of 7.1 Family Studies young healthy individuals free of traditional cardiovascular Classical family study design can overlook non-additive risk factors [75, 149]. NOS3 regulation involves receptor- genetic effects and shared environmental factors. Addi - mediated mechanisms (e.g. acetylcholine, bradykinin, and tionally, the underlying assumption regarding the genetic substance P) and mechanical stimuli (shear stress). How- relationship is flawed; offspring tend to inherit long seg - ever, NOS3 Asp298 is not unique; more than 100 poly- ments of DNA resulting in deviations from the expected morphisms in NOS3 have been identified [150], with small 50% DNA inheritance from each parent. Furthermore, Craig et al. Artery Research (2022) 28:61–78 74 family studies often recruit based on participant phe-8 Vascular phenotype notype, with family members then invited to partici- Various genes in Table 2 appear numerous times sug- pate. However, techniques to correct for ascertainment gesting effects on multiple vascular function assessment bias should be employed, such as Hopper and Mathews techniques. For example ACE, which cleaves angiotensin method which adjusts the heritability estimate based on I into angiotensin II with vasoconstrictive effects; ACE the mean and total variance of the genetic and environ- also stimulates the production of aldosterone, increas- mental components for each individual family grouping ing absorption of salt and water in the kidneys; ACE fur- [153]. thermore causes inactivation of the vasoactive mediator bradykinin. It is therefore not surprising that genetic poly- morphisms of ACE impact on many of the vascular assess- 7.2 Missing Heritability ment techniques described. Similarly, NOS3 (endothelial Another issue is ‘missing heritability’, i.e., the disparity nitric oxide synthase) has been identified as relevant in between heritability estimates derived from genotype data multiple assessment tools of vascular function, with local (explaining a low proportion of the variance), and from vasodilatory regulation of vascular tone and diameter (see twin studies (estimating significantly higher heritability). Table 2). Other genes or polymorphisms appear specific Missing heritability is likely a consequence of restriction to the technique or vascular trait, such as SAA1 in CIMT, of many genetic association studies to SNPs—missing COL4A in arterial stiffness (PWV), and CYBA encod- rare mutations. Gene-by-gene interactions, epigenetics, ing p22phox, a component of NADPH oxidase in FMD. and gene-by-environment interactions also contribute Some furthermore show a gene by sex interaction, such to missing heritability, through assumptions that such as VCAN locus in females, encoding a chondroitin sul- interactions are minimal, identifiable, and that variance fate proteoglycan of the adventitia and intima in CIMT explained by shared environmental factors is identical in [44], and NOS3 rs1799983 relating to central pulse pres- pairs. Such assumptions risk inflating heritability estimates sure and forward wave amplitude parameters again only by attributing the contribution of environmental factors to in females [98]. Others appear to only reach significance in genetics. those with hypertension, suggesting gene by gene or gene by environment interactions e.g. CYBA T allele associated with higher FMD only in hypertensive individuals [154]. These highlight the importance of comprehensive demo - 7.3 Directionality graphic reporting and consideration of such factors when Directionality is an inherent challenge when assessing comparing data from multiple sources. Finally, fewer stud- genotypic influences effecting vascular traits: differentiat - ies were identified reporting the genetics of measures of ing if an identified gene has a direct impact on e.g., PWV, endothelial function (FMD and PAT) compared to those or alternatively elevates BP which in turn leads to arterial relating to vascular stiffness and remodeling/atherosclero - remodeling, stiffness, and results in elevated PWV. The sis; we would propose this as an area for future study. Of high proportion of identified genetic loci and candidate note, no single gene or SNP discussed here demonstrates a genes common to both vascular phenotypes and hyperten- substantial association with the vascular traits and assess- sion outlined in Table 2 and Fig. 2 highlights this. ment techniques covered. This is to be expected in poly - genic traits, but may also reflect features of study design identified above: necessity for standardised technique with 7.4 Design these tools, underpowering and lack of external validation Most data are cross-sectional in nature, from which cohorts among many studies, gene–gene or gene– envi- change over time in vascular function or BP cannot be ronment interactions. Comparisons between different inferred. One might also hypothesize that SNPs contribut- demographic groups are also complicated if age, sex, race, ing to vascular ageing for example may influence PWV at and BP are not fully adjusted for. Researchers should be 60 years of age, but not at 30. Studies that do report her- cognizant of these in future studies. itability of baseline measures and progression, have found discrepancies [40]; therefore, duration of follow up, or population age of cross-sectional data must be reported in detail. Future studies independently confirming heritabil -9 Sex‑Differences ity of vascular traits and candidate genes, as well as their Gene-by-sex interaction may not always be captured by independence from each other and from BP are required, GWAS. Efforts to elucidate sex-specific genomic deter - and will determine the utility of vascular assessment tech- minants of BP demonstrated in 120 Canadian families niques as surrogate endpoints in trials, separate from their found that one quarter of the 539 hemodynamic, anthro- use as predictive risk tools. pometric, metabolic, and humoral traits studied were C raig et al. Artery Research (2022) 28:61–78 75 Funding both age and sex dependent, and one eighth were exclu- E. Murray received European Research Council funding to undertake an MD as sively age or sex dependent [155]. part of the Inflammatension Study (Grant number ERC-2016-COG awarded to A vascular phenotypic divide related to participant Prof T Guzik). sex may also exist, demonstrating greater discrimina- Data Availability tion between normotensive and hypertensive PWV and All data pertaining to this manuscript are already freely available and full refer- augmentation index for females than males [16] and sup- ences including DOI have been provided to facilitate access to data. ported by our own unit’s experience (unpublished). Con- versely, a collaboration establishing reference values for Declarations PWV describe apparent sex differences being almost fully Conflict of interest accounted for by age and BP differences [156]. Two points The authors have no conflicts of interest to disclose. therefore to consider if undertaking or analysing vascular Ethics Approval function data, is whether the groups were well matched or As a review of published literature, ethics approval was not required. adjustments for age and BP applied, and we suggest that researchers should also report outcome data stratified by Consent for Publication Not applicable. sex to facilitate interpretation. Received: 15 August 2021 Accepted: 26 April 2022 Published online: 1 June 2022 10 Conclusion In conclusion, CIMT, PWV/PWA, FMD and PAT offer utility as surrogate markers of atherosclerosis, arterial References 1. UK, “Office of National Statistics,” www. ons. gov. uk , 2020. stiffening, endothelial and microcirculatory function i.e. 2. C Vlachopoulos et al. The role of vascular biomarkers for primary and vascular function, and are predictive of cardiovascular secondary prevention. A position paper from the European society of risk. 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Artery Research – Springer Journals

Published: Jun 1, 2022

Keywords: Heritability; Genetic; Vascular; Arterial stiffening; Endothelial; CIMT

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A Review of Vascular Traits and Assessment Techniques, and Their Heritability

A Review of Vascular Traits and Assessment Techniques, and Their Heritability

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A Review of Vascular Traits and Assessment Techniques, and Their Heritability

A Review of Vascular Traits and Assessment Techniques, and Their Heritability

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