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Table 2 Gene polymorphisms relating to techniques measuring vascular health, with consideration of sex differences and heritability estimates

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

CIMT Candidate Genes with implicated role

Design

Evidence of BP association

ATG10—E2-like enzyme involved in 2 ubiquitin-like modifications essential for autophagosome formation Strawbridge 2020 [44]

GWAS (UK Biobank)

N/A

RPS23—encodes a ribosomal protein Strawbridge 2020[44]

GWAS (UK Biobank)

N/A

ATP6AP1L—ATPase H + Transporting Accessory Protein 1 Like, a protein coding gene; Strawbridge 2020[44]

GWAS (UK Biobank)

N/A

MIR8055 and MIR4693—RNA Genes affiliated with the miRNA class; Strawbridge 2020 [44]

GWAS (UK Biobank)

N/A

CBFA2T3—encodes a myeloid translocation gene family member which interact to repress transcription; Strawbridge 2020 [44]

GWAS (UK Biobank)

Larsson 2013 [58]

CYP2A6 and CYP2A7- encodes a member of the cytochrome P450 superfamily of enzymes; Strawbridge 2020 [44]

GWAS (UK Biobank)

Liu 2013 [59]

APOE E2 allele encodes a major apoprotein of the chylomicron. Natarajan 2016; Bis 2011; Strawbridge 2020. [44, 60, 61]

Meta-analysis of exome-WAS & GWAS (CHARGE)

N/A

BCAM—basal cell adhesion molecule; encodes Lutheran blood group glycoprotein, a member of the immunoglobulin superfamily and a receptor for laminin Starwbridge 2020, Bis 2011 [44, 61]

Meta-analysis of GWAS (CHARGE)

N/A

ZHX2—acts as a transcriptional repressor, rs11781551 associated with lower CIMT; Bis 2011 [61]

Meta-analysis of GWAS (CHARGE)

N/A

APOC1—expressed primarily in the liver, activated when monocytes differentiate into macrophages Bis 2011 [61]

Meta-analysis of GWAS (CHARGE)

N/A

PINX1—Microtubule-binding protein essential for chromosome segregation, 1rs6601530 copy number associated with higher CIMT; Bis 2011 [61]

Meta-analysis of GWAS (CHARGE)

Feitosa 2018 [62]

PIK3CG—phosphorylate inositol lipids involved in immune response, rs17398575 associated with 18% increased odds of plaque Bis 2011 [61], not supported by López-Mejías 2014 [63]

Meta-analysis of GWAS (CHARGE)

Carnevale 2012 [64]

EDNRA—encodes the receptor for endothelin-1; role in vasoconstriction; rs1878406 associated with 22% increased odds of plaque; Bis 2011[61]; not supported by López-Mejías 2014 [63]

Meta-analysis of GWAS (CHARGE)

Hoffman 2017 [65]

ADAMTS7—a member of the ADAMTS family, a disintegrin and metalloproteinase with thrombospondin motifs; van Setten et al., 2013 [67], not supported by López-Mejías 2014 [63]

GWAS (Dutch and Belgian Lung Cancer Screening population)

Warren 2017 [66], Wirtwein 2017 [68]

THBS2—thrombospondin 2, a disulfide-linked homotrimeric glycoprotein that mediates cell-to-cell and cell-to-matrix interactions; McCarthy 2004 [69]

GWAS (GeneQuest, USA)

Oguri 2009 [66]

CFDP1—protein coding gene, may play a role during embryogenesis; Gertow, 2012 [70]

GWAS (IMPROVE population, European)

The UK Biobank Cardio-metabolic Traits Consortium Blood Pressure Working Group [66]

SLC17A2—involved in phosphate transport into cells; rs17526722 associated with lower CIMT in Mexican-Americans. Arya 2018 [71]

GWAS (RA patients)

N/A

PPCDC—necessary for biosynthesis of coenzyme A; rs1867148 associated with lower CIMT in European-Americans; Arya 2018 [71]

GWAS (RA patients)

Nandakumar 2019 [72]

PNPT1—RNA-binding protein involved in multiple processes e.g. importing RNA into mitochondria. Vojinovic 2018 [73]

GWAS (Erasmus Rucphen Family)

Ali 2019 [74]

NOS3—nitric oxide has a role in vascular tone; Asp/Asp genotype demonstrated greater CIMT (P = 0.0002) Paradossi 2004 [75]

Candidate gene study

Hoffman 2016 [65], Nassereddine 2018 [76], Giri [77], and others

SAA1 (rs12218) and SSA2 (rs2468844)—acute phase protein, associated with CIMT in healthy Chinese population Xie 2010[48]

Candidate gene study

N/A

MMP9—involved in the breakdown of extracellular matrix; associated with internal carotid but not common carotid artery IMT Armstrong 2007[42],

Candidate gene study

Dhingra 2016 [78]

MMP3—involved in the breakdown of extracellular matrix; relationship between increasing copy number and CIMT Armstrong 2007[42]

Candidate gene study

Armstrong 2007 [42] Beilby 2005 [79]

TIMP3—inactivates metalloproteinases; shows relationship between increasing copy number and CIMT. Armstrong 2007[42]

Candidate gene study

Armstrong 2007 [42]

CXCL12—arterial remodeling and thickening, rs1746048 associated with IMT. Zabalza 2015[43]

Candidate gene study

Liu 2018 [80]

WDR12—involved in cell cycle/proliferation, signal transduction and gene regulation; inverse association with CIMT; Zabalza 2015 [43]

Candidate gene study

Wirtwein 2017 [68]

CYBA encodes p22phox, a component of NADPH oxidase. C242T polymorphism was a predictor of internal CIMT following multivariable adjustment (b-coefficient − 0.119, p = 0.011). Lambrinoudaki 2018[81]

Candidate gene study

N/A

GCKR—product is a regulatory protein that inhibits glucokinase in liver and pancreatic islet cells; rs780094 associated with carotid plaque in the American Indian but not European-, African-, or Mexican–American populations Zhang 2013[82]

Candidate gene study

N/A

ADAM33—transmembrane protein, role in inflammation and regeneration; rs514174 associated with CIMT; Zhang 2019[83]

Candidate gene study

N/A

TRAF1—adapter molecule that regulates the activation of NF-kappa-B and JNK, Heßler 2016[84]

Linkage analysis

N/A

SMOC-1—glycoprotein mediating cell–matrix interactions Sacco 2009 [39]

Linkage analysis

N/A

FBLN5—secreted protein involved in cell adhesion Sacco 2009 [39]

Linkage analysis

N/A

CIMT Studies reporting sex-specific findings

Design

Evidence of BP association

VCAN—female-specific locus; encodes a chondroitin sulfate proteoglycan of the adventitia and intima. Strawbridge 2020 [44]

GWAS (UK Biobank)

N/A

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 2019[85, 86]

GWAS (UK BioBank)

Zekavat 2019 included causal inference analyses with BP [85]. Also Warren 2017 [66]

FOXO1 (rs7331212)—role in T lymphocyte function and cell cycle regulation including osteogenesis and angiogenesis. Zekavat 2019, Fung 2019 [85, 86]

GWAS (UK BioBank)

Animal model Qi 2014 [87]

MRVI1 (rs10840457), synonym: IRAG. Role as regulator of IP3-induced calcium release in platelet activation and NO-dependent smooth muscle relaxation. Fung 2019[86]

GWAS (UK BioBank)

Animal model association with BP: Desch 2010 [88]; association not evidenced in human studies

COL4A1 and COL4A2 (rs3742207, rs9521719, rs872588)—type 4 collagen and associated with arterial stiffness (by PulseTrace PCA2); Zekavat 2019 and Fung 2019 [85, 86]; Tarasov 2009 [89]

GWAS (UK BioBank and SardiNIA)

N/A

TCF20 (rs55906806): transcription factor recognises platelet-derived growth factor-responsive element in MMP3 promoter. Zekavat 2019 and Fung 2019[85, 86]

GWAS (UK BioBank)

N/A

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. scaffolding protein; associated with PWV. Tarasov 2009 [89]

GWAS (SardiNIA)

Levy 2007 [91]

BCL11B (rs7152623) role in immune regulation; linked to carotid-femoral PWV and CVD. Mitchell 2012[92]

Meta-analysis of 9 European ancestry GWAS

Association with nocturnal dipping (GENRES (n = 204), DYNAMIC (n = 183) and DILGOM cohorts (n = 180) Rimpelä 2018 [93]

IL6 (pro-inflammatory cytokine). Mitchell 2005 [52](Framingham Study offspring cohort, n = 1480)

GWAS (Framingham)

N/A

PHACTR1 (rs9349379) regulates cytoskeleton; G allele linked to decreased arterial stiffness (PulseTrace PCA2) Zekavat 2019[85]

GWAS (UK BioBank)

Gupta 2017,n = 38,817 (UK BioBank) [94]

IGF1R (insulin-like growth factor 1 receptor) complex effects on vasculature including cellular proliferation, vasodilation via NO, and other endothelial functions. Mitchell 2005 [52]

GWAS (Framingham)

Schutte 2014 [95]

MEF2A (myocyte-specific enhancer factor 2A), DNA-binding transcription factor, activates growth factor and stress-induced genes. Mitchell 2005[52]

GWAS (Framingham)

Evangelou 2018 [90]; Giri 2018 [77]

CHSY1 (chondroitin synthase 1), role in biosynthesis of chondroitin sulfate, a glycosaminoglycan required for cell proliferation and morphogenesis. Mitchell 2005[52]

GWAS (Framingham)

N/A

PACE4 (PCSK6) and FURIN, encodes a protease with multiple substrates including pro-hormones, growth factors and von Willebrand factor; Mitchell 2005 [52]

GWAS (Framingham)

Li 2004 [96]; Ehret 2011 [97]

ADD2 (β-adducin), encode subunits of membrane skeletal proteins. Mitchell 2005[52]

GWAS (Framingham)

N/A

TACR1 (tachykinin/neurokinin-1 receptor) encodes receptor for and mediates metabolism of tachykinin substance P. Mitchell 2005[52]

GWAS (Framingham)

N/A

ADRA2B (beta adrenergic receptor) mediate catecholamine-induced inhibition of adenylate cyclase through G proteins; Mitchell 2005[52]

GWAS (Framingham)

N/A

NOS3 rs1799983 related to central pulse pressure and forward wave amplitude parameters of PWA) in females only. Mitchell 2007[98])

Candidate gene study

Hoffman 2016 [65], Nassereddine 2018 [76], Giri 2018 [77] and others

TXNIP (rs7212) G allele associated with higher PWV values; functions as sensor for biomechanical and oxidative stress. Alvim 2011[99] (Brazilian cohort, n = 1518)

Candidate gene study (Brazilian cohort)

N/A

COL1A1 polymorphisms—collagen type 1A deposition in arterial compliance. Brull 2001[100] (Young Hearts Project, UK, N = 489)

Candidate gene study

N/A

ETAR (Endothelin-A and -B receptor, synonym EDNRA); endothelin being a vasoconstrictor; gene variants influenced PWV. Lajemi 2001[101] (n = 528, untreated hypertensive Europeans)

Candidate gene study

Hoffman et l 2016 [65]

ACE I/D (rs4340)—role in BP regulation and electrolyte balance through 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]

Candidate gene studies

Hoffman 2016 [65]; Sie 2009 [110], and others

AGTR1 (AT II type 1 receptor)—AT II acts as a vasoconstrictor and regulates 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]

Candidate gene studies

Numerous, see www.ensembl.org; e.g. Bonnardeaux 1994 [112]

AGT (angiotensinogen) gene, M235T polymorphism associated with arterial stiffness in 98 untreated hypertensive individuals. Bozec 2004[111]

Candidate gene study

Hoffman 2016 [65]; Sie 2009 [110], and others

PWV and PWA Studies reporting sex-specific findings

Design

Evidence of BP association

FBN1 (Fibrillin-1) 2/3 genotype associated with higher PWA AIx and BP in females only. Malm 2020[114] (n = 315 hypertensive elderly subjects); Medley 2002[115] (n = 145)

Candidate gene study

Malm 2020 [114]; Medley 2002 [115]

PAT Candidate Genes with implicated role

Design

Evidence of BP association

CSK—cytoplasmic tyrosine kinase, role in angiotensin II-mediated vascular smooth muscle contraction (Hong 2010)[116]

GWAS (KARE)

Hong 2009 [116]

NOS3 (eNOS)—produces nitric oxide which is implicated in vascular smooth muscle relaxation; (Burghardt 2017)[117]

Candidate gene study

Hoffman 2016 [65], Giri 2018 [77] and others

APOE3/E4—a protein which is a component of lipoprotein (Korsakova 2018)[118]

Candidate gene study

N/A

ACE—converts angiotensin I to angiotensin II, resulting in increased vasoconstrictor activity; (Korsakova 2018)[118]

Candidate gene study

Montrezol 2019 [119]; Hoffman 2016 [65]; Sie 2009 [110], and others

SPHK 1—modulates Ang II-dependent vascular dysfunction; (Siedlinski et at., 2017)[120]

Animal model/human data

Pietro 2020 [121] (animal and human data)

ADORA1—receptor for adenosine, activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase (Yoshino 2016)[122]

Linkage analysis

Evangelou 2018 [90]

PAT Theorised genes, but data lacking

Design

Evidence of BP association

SH2B3—LNK, lymphocyte-specific adaptor protein; endothelial cell function and vascular regeneration, though not specifically reported in EndoPAT (Newton-Cheh 2009; McMaster 2014 animal model)[123, 124]

GWAS (Global BPgen & CHARGE consortiums)

Dale 2016 [125]; Newton-Cheh 2009 [123], Ference 2014 [126]

PAT Studies reporting sex-specific findings

Design

Evidence of BP association

ADORA3 strongest associations in women (member of the adenosine receptor group of G-protein-coupled receptors) (Yoshino 2016)[122]

Linkage analysis

N/A

LPA strongest associations in women (protein encoded by this gene is a serine proteinase that inhibits the activity of tissue-type plasminogen activator I) (Yoshino 2016)[122]

Linkage analysis

Smyth 2008 [127], Wirtwein 2017 [68]

KIF6 strongest associations in men (encodes a member of a family of molecular motors which are involved in intracellular transport of protein complexes) (Yoshino 2016)[122]

Linkage analysis

N/A

NFKB1 strongest associations in men (a rapidly acting primary transcription factor found in all cell types) (Yoshino 2016)[122]

Linkage analysis

N/A

FMD Candidate Genes with implicated role

Design

Evidence of BP association

PHACTR1 (rs9349379): encoded protein binds actin and 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]

Candidate gene study

Gu 2020 [128]; Zhang 2012 [129]

NOS3 ( eNOS): Glu298 → Asp polymorphism—Nitric oxide has a role in vascular tone; associated with FMD Paradossi 2004, n = 118; and Ingelsson 2008, n = 959 [75, 130]

Candidate gene study

Hoffman 2016 [65], Nassereddine 2018 [76], Giri 2018 [77] and others

CD36 (rs3211938): integral membrane protein expressed by 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]

Candidate gene study

Xueyan 2013 [132]

AT1R (synonym AGTR1): AT II acts as a vasoconstrictor and regulates aldosterone, hence blood volume: FMD reduced in C allele carriers Li et al. 2015, and Akpinar et al., 2014, n = 255 [133]

Candidate gene study

Numerous, see www.ensembl.org; e.g. Bonnardeaux 1994 [112]

CYBA (C242T polymorphism) encodes p22phox, a component 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]

Candidate gene study

N/A

APOE: FMD associated with E4 allele in stepwise regression analysis. Guangda 2003, n = 255 with diabetes [136]

Candidate gene study

N/A

NFKB1: encoding NFKB protein, a transcription regulator; reduced reactive forearm blood flow identified in DD genotype; Park 2007, n = 47

Candidate gene study

N/A

PDE3A: Phosphodiesterases regulate endothelial function and smooth muscle contraction through role in the NO/cGMP pathway. Traylor 2020; ALSPAC (Avon Longitudinal Study of Parents and Children; n = 5214, integrated with MEGASTROKE: n = 60,341) [137]

Linkage analysis

Associated with hypertension and brachydactyly syndrome. Maass 2015 [138]; Luft 2019 [139]

FMD Theorised genes, but data lacking or no association found

Design

Evidence of BP association

SH2B3 (LNK—lymphocyte-specific adaptor protein)—endothelial cell function and vascular regeneration, not specifically reported in FMD. Newton-Cheh 2009, also McMaster 2014 [123]

GWAS (Global BPgen and CHARGE consortiums)

Levy 2009 [140]; Ference 2014 [126], Hoffman 2016 [65]; Ehret 2016 [113] and others

ACE gene: mostly endothelial-bound, role in BP regulation and electrolyte balance through hydrolyzing angiotensin I; no effect on FMD. Akpinar 2014 and Celermajer 1994 [133, 141]

Candidate gene study

Hoffman 2016 [65]; Sie 2009 [110], and others

FMD Studies reporting sex-specific findings

Design

Evidence of BP association

Sex-specific multivariable models estimated similar effects of age on baseline artery diameter and FMD in mm for both 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]

GWAS (Global BPgen and CHARGE consortiums)

Levy 2009 [140]; Ference 2014 [126], Hoffman 2016 [65]; Ehret 2016 [113] and others

ACE gene: mostly endothelial-bound, role in BP regulation and electrolyte balance through hydrolyzing angiotensin I; no effect on FMD. Akpinar 2014 and Celermajer 1994 [133, 141]

N/A

 
  1. 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)