Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2016 Dec;9(6):511-520.
doi: 10.1161/CIRCGENETICS.116.001572. Epub 2016 Nov 21.

Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Pradeep NatarajanJoshua C BisLawrence F BielakAmanda J CoxMarcus DörrMary F FeitosaNora FranceschiniXiuqing GuoShih-Jen HwangAaron IsaacsMin A JhunMaryam KavousiRuifang Li-GaoLeo-Pekka LyytikäinenRiccardo E MarioniUlf SchminkeNathan O StitzielHayato TadaJessica van SettenAlbert V SmithDina VojinovicLisa R YanekJie YaoLaura M Yerges-ArmstrongNajaf AminUsman BaberIngrid B BoreckiJ Jeffrey CarrYii-Der Ida ChenL Adrienne CupplesPim A de JongHarry de KoningBob D de VosAyse DemirkanValentin FusterOscar H FrancoMark O GoodarziTamara B HarrisSusan R HeckbertGerardo HeissUdo HoffmannAlbert HofmanIvana IšgumJ Wouter JukemaMika KähönenSharon L R KardiaBrian G KralLenore J LaunerJoe MassaroRoxana MehranBraxton D MitchellThomas H Mosley JrRenée de MutsertAnne B NewmanKhanh-Dung NguyenKari E NorthJeffrey R O'ConnellMatthijs OudkerkJames S PankowGina M PelosoWendy PostMichael A ProvinceLaura M RaffieldOlli T RaitakariDermot F ReillyFernando RivadeneiraFrits RosendaalSamantha SartoriKent D TaylorAlexander TeumerStella TrompetStephen T TurnerAndre G UitterlindenDhananjay VaidyaAad van der LugtUwe VölkerJoanna M WardlawChristina L WasselStefan WeissMary K WojczynskiDiane M BeckerLewis C BeckerEric BoerwinkleDonald W BowdenIan J DearyAbbas DehghanStephan B FelixVilmundur GudnasonTerho LehtimäkiRasika MathiasDennis O Mook-KanamoriBruce M PsatyDaniel J RaderJerome I RotterJames G WilsonCornelia M van DuijnHenry VölzkeSekar KathiresanPatricia A PeyserChristopher J O'DonnellCHARGE Consortium
Free PMC article
Meta-Analysis

Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Pradeep Natarajan et al. Circ Cardiovasc Genet. .
Free PMC article

Abstract

Background: The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease.

Methods and results: We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3×10-10). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1×10-12) and 1.4% reduced carotid intima-media thickness (P=4×10-14) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1×10-11).

Conclusions: Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

Keywords: carotid intima–media thickness; coronary artery calcification; exome; genome-wide association study; genomics.

Figures

Figure 1
Figure 1
Association of each genotyped variant with CAC quantity. Plot of -log10(P) for association of genotyped variants by chromosomal position for all autosomal polymorphisms analyzed in the age-, sex-, and principal components- adjusted model of coronary artery calcification quantity in the meta-analysis. The genes associated with the top associated variants are displayed.
Figure 2
Figure 2
Forest plot of relative CAC quantity for APOE ε2 carriers. CAC quantity for APOE ε2 carriers relative to non-carriers is displayed for all cohorts stratified by European and African ancestries to demonstrate consistency across diverse cohorts and ethnicities.
Figure 3
Figure 3
Association of each genotyped variant with CIMT. Plot of -log10(P) for association of genotyped variants by chromosomal position for all autosomal polymorphisms analyzed in the age-, sex-, and principal components- adjusted model of carotid intima media thickness in the meta-analysis. The genes associated with the top associated variants are displayed.
Figure 4
Figure 4
Forest plot of relative CIMT for APOE ε2 carriers. CIMT for APOE ε2 carriers relative to non-carriers is displayed for all cohorts stratified by European and African ancestries to demonstrate consistency across diverse cohorts and ethnicities.

Similar articles

See all similar articles

Cited by 15 articles

See all "Cited by" articles

MeSH terms

Feedback