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Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.

TitleAssociation between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.
Publication TypeJournal Article
Year of Publication2012
AuthorsMurabito JM, White CC, Kavousi M, et al.
Secondary AuthorsKronenberg F
JournalCirc Cardiovasc Genet
Volume5
Issue1
Pagination100-12
Date Published2012 Feb 01
ISSN1942-3268
KeywordsAdult, Age Factors, Aged, Aged, 80 and over, Alleles, Ankle Brachial Index, Chromosomes, Human, Pair 9, Cohort Studies, Cyclin-Dependent Kinase Inhibitor p15, Female, Genome-Wide Association Study, Genotype, HapMap Project, Humans, Logistic Models, Male, Middle Aged, Peripheral Vascular Diseases, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Sex Factors
Abstract

BACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.

METHODS AND RESULTS: Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).

CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.

DOI10.1161/CIRCGENETICS.111.961292
Alternate JournalCirc Cardiovasc Genet
PubMed ID22199011
PubMed Central IDPMC3303225
Grant ListHHSN268201100009I / HL / NHLBI NIH HHS / United States
M01-RR00425 / RR / NCRR NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
N01 HC-95169 / HC / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
HL08770002 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
CZB/4/710 / / Chief Scientist Office / United Kingdom
N01-AG-12111 / AG / NIA NIH HHS / United States
R01 HL075366 / HL / NHLBI NIH HHS / United States
N01 HC-95165 / HC / NHLBI NIH HHS / United States
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