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Genetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium.

Monday,2013-04-22 18:06 America/Los_Angeles — eenright
TitleGenetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium.
Publication TypeJournal Article
Year of Publication2012
AuthorsWassel, CL, Lamina, C, Nambi, V, Coassin, S, Mukamal, KJ, Ganesh, SK, Jacobs, DR, Franceschini, N, Papanicolaou, GJ, Gibson, Q, Yanek, LR, van der Harst, P, Ferguson, JF, Crawford, DC, Waite, LL, Allison, MA, Criqui, MH, McDermott, MM, Mehra, R, Cupples, AL, Hwang, S-J, Redline, S, Kaplan, RC, Heiss, G, Rotter, JI, Boerwinkle, E, Taylor, HA, Eraso, LH, Haun, M, Li, M, Meisinger, C, O'Connell, JR, Shuldiner, AR, Tybjærg-Hansen, A, Frikke-Schmidt, R, Kollerits, B, Rantner, B, Dieplinger, B, Stadler, M, Mueller, T, Haltmayer, M, Klein-Weigel, P, Summerer, M, Wichmann, H-E, Asselbergs, FW, Navis, G, Leach, IMateo, Brown-Gentry, K, Goodloe, R, Assimes, TL, Becker, DM, Cooke, JP, Absher, DM, Olin, JW, Mitchell, BD, Reilly, MP, Mohler, ER, North, KE, Reiner, AP, Kronenberg, F, Murabito, JM
JournalAtherosclerosis
Volume222
Issue1
Pagination138-47
Date Published2012 May
ISSN1879-1484
KeywordsAdult, African Americans, Aged, Ankle Brachial Index, Aryl Hydrocarbon Hydroxylases, Cytochrome P-450 CYP2B6, European Continental Ancestry Group, Female, Humans, Male, Middle Aged, Oxidoreductases, N-Demethylating, Peripheral Arterial Disease, Polymorphism, Single Nucleotide, Risk Factors, Transcription Factor 7-Like 2 Protein
Abstract<p><b>BACKGROUND: </b>Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI.</p><p><b>METHODS AND RESULTS: </b>We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance.</p><p><b>RESULTS: </b>In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.</p><p><b>CONCLUSIONS: </b>Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.</p>
DOI10.1016/j.atherosclerosis.2012.01.039
Alternate JournalAtherosclerosis
PubMed ID22361517
PubMed Central IDPMC3596171
Grant ListR01 HL071025 / HL / NHLBI NIH HHS / United States
N01 HC055022 / HC / NHLBI NIH HHS / United States
R01 HL075366 / HL / NHLBI NIH HHS / United States
R01 AG015928-02 / AG / NIA NIH HHS / United States
R01 HL059367-11 / HL / NHLBI NIH HHS / United States
UL1 RR024156-06 / RR / NCRR NIH HHS / United States
R01 HL087698 / HL / NHLBI NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
R01 NR008153 / NR / NINR NIH HHS / United States
U01 HL080295-04 / HL / NHLBI NIH HHS / United States
R01 HL087652-03 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
UL1 RR025005-05 / RR / NCRR NIH HHS / United States
R01 NR008153-04 / NR / NINR NIH HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
N01HC95163 / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
M01 RR000052-46 / RR / NCRR NIH HHS / United States
N01 HC075150 / HC / NHLBI NIH HHS / United States
M01 RR000070-46 / RR / NCRR NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
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N01 HC015103 / HC / NHLBI NIH HHS / United States
N01HC95169 / HL / NHLBI NIH HHS / United States
R01 AG027058-04 / AG / NIA NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
N01 HC095161 / HC / NHLBI NIH HHS / United States
N01 HC065226 / HC / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
UL1 RR024156 / RR / NCRR NIH HHS / United States
R01 HL086694-05 / HL / NHLBI NIH HHS / United States
R18 HL058625-02 / HL / NHLBI NIH HHS / United States
N01 HC085085 / HC / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
M01 RR008084 / RR / NCRR NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
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UL1 TR000124 / TR / NCATS NIH HHS / United States
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R01 HL075366-05 / HL / NHLBI NIH HHS / United States
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R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HL059684-04 / HL / NHLBI NIH HHS / United States
R01 NR002241 / NR / NINR NIH HHS / United States
N01 HC055019 / HC / NHLBI NIH HHS / United States
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P50 HL083800 / HL / NHLBI NIH HHS / United States
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N01HC85080 / HL / NHLBI NIH HHS / United States
5215810-55000000041 / / PHS HHS / United States
P50 HL083800-05 / HL / NHLBI NIH HHS / United States
P30 DK072488-04S1 / DK / NIDDK NIH HHS / United States
R01 HL087698-03W1 / HL / NHLBI NIH HHS / United States
U01 GM074518 / GM / NIGMS NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States
N01 HC095159 / HC / NHLBI NIH HHS / United States
U01 HL072518-06 / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
UL1 RR024134 / RR / NCRR NIH HHS / United States
R01 HL088119 / HL / NHLBI NIH HHS / United States
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