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.

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.

Dana C Crawford | Florian Kronenberg | Eric Boerwinkle | Themistocles L Assimes | Robert J. Goodloe | George J Papanicolaou | Susan Redline | Anne Tybjærg-Hansen | Muredach P Reilly | Christa Meisinger | Kristin Brown-Gentry | Nora Franceschini | Claudia Lamina | Barbara Kollerits | Vijay Nambi | L Adrienne Cupples | Braxton D Mitchell | Jeffrey R O'Connell | Pim van der Harst | Kari E North | Gerardo Heiss | Folkert W Asselbergs | Emile R Mohler | Margot Haun | Stefan Coassin | Thomas Mueller | J. Murabito | F. Kronenberg | D. Absher | T. Assimes | A. Reiner | S. Redline | Mingyao Li | E. Boerwinkle | J. O’Connell | Shih-Jen Hwang | M. Reilly | D. Jacobs | H. Wichmann | C. Meisinger | J. Rotter | S. Coassin | M. Criqui | D. Becker | G. Papanicolaou | L. Cupples | M. McDermott | R. Mehra | D. Crawford | G. Heiss | K. North | J. Cooke | L. Waite | N. Franceschini | L. Yanek | P. van der Harst | A. Shuldiner | S. Ganesh | B. Mitchell | E. Mohler | G. Navis | K. Brown-Gentry | B. Rantner | Q. Gibson | R. Kaplan | F. Asselbergs | M. Allison | R. Frikke-Schmidt | C. Lamina | H. Taylor | I. Mateo Leach | J. Ferguson | T. Mueller | B. Dieplinger | M. Haltmayer | R. Goodloe | M. Haun | B. Kollerits | J. Olin | C. Wassel | A. Tybjærg‐Hansen | K. Mukamal | P. Klein-Weigel | M. Summerer | Marietta Stadler | Diane M Becker | Benjamin Dieplinger | Meinhard Haltmayer | Michael H Criqui | Ruth Frikke-Schmidt | Robert Goodloe | Alan R Shuldiner | Alexander P Reiner | Shih-Jen Hwang | Joanne M Murabito | Jerome I Rotter | Christina L Wassel | Matthew A Allison | H-Erich Wichmann | Lisa R Yanek | Santhi K Ganesh | Gerjan Navis | Robert C Kaplan | Mingyao Li | Herman A Taylor | Devin M Absher | Irene Mateo Leach | Jeffrey W Olin | Kenneth J Mukamal | John P Cooke | Jane F Ferguson | David R Jacobs | M. Stadler | Reena Mehra | L. Eraso | Mary M McDermott | Lindsay L Waite | Quince Gibson | Luis H Eraso | Barbara Rantner | Peter Klein-Weigel | Monika Summerer | V. Nambi | P. van der harst | Irene Mateo Leach

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