TY - JOUR
T1 - Genetic determinants of the ankle-brachial index
T2 - A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium
AU - Wassel, Christina L.
AU - Lamina, Claudia
AU - Nambi, Vijay
AU - Coassin, Stefan
AU - Mukamal, Kenneth J.
AU - Ganesh, Santhi K.
AU - Jacobs, David R.
AU - Franceschini, Nora
AU - Papanicolaou, George J.
AU - Gibson, Quince
AU - Yanek, Lisa R.
AU - van der Harst, Pim
AU - Ferguson, Jane F.
AU - Crawford, Dana C.
AU - Waite, Lindsay L.
AU - Allison, Matthew A.
AU - Criqui, Michael H.
AU - McDermott, Mary M.
AU - Mehra, Reena
AU - Cupples, L. Adrienne
AU - Hwang, Shih Jen
AU - Redline, Susan
AU - Kaplan, Robert C.
AU - Heiss, Gerardo
AU - Rotter, Jerome I.
AU - Boerwinkle, Eric
AU - Taylor, Herman A.
AU - Eraso, Luis H.
AU - Haun, Margot
AU - Li, Mingyao
AU - Meisinger, Christa
AU - O'Connell, Jeffrey R.
AU - Shuldiner, Alan R.
AU - Tybjærg-Hansen, Anne
AU - Frikke-Schmidt, Ruth
AU - Kollerits, Barbara
AU - Rantner, Barbara
AU - Dieplinger, Benjamin
AU - Stadler, Marietta
AU - Mueller, Thomas
AU - Haltmayer, Meinhard
AU - Klein-Weigel, Peter
AU - Summerer, Monika
AU - Wichmann, H. Erich
AU - Asselbergs, Folkert W.
AU - Navis, Gerjan
AU - Leach, Irene Mateo
AU - Brown-Gentry, Kristin
AU - Goodloe, Robert
AU - Assimes, Themistocles L.
AU - Becker, Diane M.
AU - Cooke, John P.
AU - Absher, Devin M.
AU - Olin, Jeffrey W.
AU - Mitchell, Braxton D.
AU - Reilly, Muredach P.
AU - Mohler, Emile R.
AU - North, Kari E.
AU - Reiner, Alexander P.
AU - Kronenberg, Florian
AU - Murabito, Joanne M.
N1 - Funding Information:
The Candidate Gene Association Resource (CARe) is supported by contract number HHSN268200625226C from the National Institutes of Health (NIH)/National Heart Lung and Blood Institute (NHLBI) , and subcontract number 5215810-55000000041 to C.L.W. A full listing of the grants and contracts that have supported CARe is provided at http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx . Please see information in supplementary information file for a complete list of funding information for each study participating in this manuscript.
PY - 2012/5
Y1 - 2012/5
N2 - Background: 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. Methods and results: 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. Results: 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. Conclusions: 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.
AB - Background: 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. Methods and results: 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. Results: 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. Conclusions: 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.
KW - Ankle brachial index
KW - Candidate gene array
KW - Ethnicity
KW - Genetics
KW - Meta-analysis
KW - Peripheral artery disease
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U2 - 10.1016/j.atherosclerosis.2012.01.039
DO - 10.1016/j.atherosclerosis.2012.01.039
M3 - Article
C2 - 22361517
AN - SCOPUS:84862819551
SN - 0021-9150
VL - 222
SP - 138
EP - 147
JO - Atherosclerosis
JF - Atherosclerosis
IS - 1
ER -
