Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project

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Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.

Vyšlo v časopise: Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project. PLoS Genet 7(2): e32767. doi:10.1371/journal.pgen.1001300
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001300

Souhrn

Zdroje

1. NHLBI 2009 2009 NHLBI Morbidity and Mortality Chart Book

2. ThomasJ

ThomasDJ

PearsonT

KlagM

MeadL

1997 Cardiovascular disease in African American and white physicians: the Meharry Cohort and Meharry-Hopkins Cohort Studies. J Health Care Poor Underserved 8 270 283; discussion 284

3. JonesDW

ChamblessLE

FolsomAR

HeissG

HutchinsonRG

2002 Risk factors for coronary heart disease in African Americans: the atherosclerosis risk in communities study, 1987–1997. Arch Intern Med 162 2565 2571

4. CooperR

RotimiC

1997 Hypertension in blacks. Am J Hypertens 10 804 812

5. CooperRS

ZhuX

2001 Racial differences and the genetics of hypertension. Curr Hypertens Rep 3 19 24

6. KatzmarzykPT

PerusseL

RiceT

GagnonJ

SkinnerJS

2000 Familial resemblance for coronary heart disease risk: the HERITAGE Family Study. Ethn Dis 10 138 147

7. WTCCC 2007 Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 661 678

8. ErdmannJ

GrosshennigA

BraundPS

KonigIR

HengstenbergC

2009 New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat Genet 41 280 282

9. HelgadottirA

ThorleifssonG

ManolescuA

GretarsdottirS

BlondalT

2007 A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316 1491 1493

10. KathiresanS

VoightBF

PurcellS

MusunuruK

ArdissinoD

2009 Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 41 334 341

11. McPhersonR

PertsemlidisA

KavaslarN

StewartA

RobertsR

2007 A common allele on chromosome 9 associated with coronary heart disease. Science 316 1488 1491

12. SamaniNJ

ErdmannJ

HallAS

HengstenbergC

ManginoM

2007 Genomewide association analysis of coronary artery disease. N Engl J Med 357 443 453

13. WillerCJ

SannaS

JacksonAU

ScuteriA

BonnycastleLL

2008 Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40 161 169

14. GudbjartssonDF

BjornsdottirUS

HalapiE

HelgadottirA

SulemP

2009 Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 41 342 347

15. MusunuruK

LettreG

YoungT

FarlowDN

PirruccelloJP

2010 Candidate gene association resource (CARe): design, methods, and proof of concept. Circ Cardiovasc Genet 3 267 275

16. KornJM

KuruvillaFG

McCarrollSA

WysokerA

NemeshJ

2008 Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat Genet 40 1253 1260

17. PriceAL

PattersonNJ

PlengeRM

WeinblattME

ShadickNA

2006 Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38 904 909

18. LiY

WillerC

SannaS

AbecasisG

2009 Genotype imputation. Annu Rev Genomics Hum Genet 10 387 406

19. KangSJ

ChiangCW

PalmerCD

TayoBO

LettreG

2010 Genome-wide association of anthropometric traits in African- and African-derived populations. Hum Mol Genet 19 2725 2738

20. PurcellS

NealeB

Todd-BrownK

ThomasL

FerreiraMA

2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575

21. ChenMH

YangQ

2009 GWAF: an R package for genome-wide association analyses with family data. Bioinformatics

22. WillerCJ

LiY

AbecasisGR

2010 METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26 2190 2191

23. HindorffLA

SethupathyP

JunkinsHA

RamosEM

MehtaJP

2009 Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 106 9362 9367

24. AdeyemoA

GerryN

ChenG

HerbertA

DoumateyA

2009 A genome-wide association study of hypertension and blood pressure in African Americans. PLoS Genet 5 e1000564 doi:10.1371/journal.pgen.1000564

25. HelgasonA

PalssonS

ThorleifssonG

GrantSF

EmilssonV

2007 Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat Genet 39 218 225

26. KathiresanS

WillerCJ

PelosoGM

DemissieS

MusunuruK

2009 Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41 56 65

27. PattersonN

HattangadiN

LaneB

LohmuellerKE

HaflerDA

2004 Methods for high-density admixture mapping of disease genes. Am J Hum Genet 74 979 1000

28. ChenMH

YangQ

2010 GWAF: an R package for genome-wide association analyses with family data. Bioinformatics 26 580 581

29. ZegginiE

ScottLJ

SaxenaR

VoightBF

MarchiniJL

2008 Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40 638 645

30. TeslovichTM

MusunuruK

SmithAV

EdmondsonAC

StylianouIM

2010 Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466 707 713

31. AulchenkoYS

RipattiS

LindqvistI

BoomsmaD

HeidIM

2009 Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 41 47 55

32. KathiresanS

MelanderO

GuiducciC

SurtiA

BurttNP

2008 Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 40 189 197

33. PruimRJ

WelchRP

SannaS

TeslovichTM

ChinesPS

2010 LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26 2336 2337