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

被引：22

作者：

Wassel, Christina L. ^{[1
]}

Lamina, Claudia ^{[2
]}

Nambi, Vijay ^{[3
]}

Coassin, Stefan ^{[2
]}

Mukamal, Kenneth J. ^{[4
]}

Ganesh, Santhi K. ^{[5
]}

Jacobs, David R., Jr. ^{[6
]}

Franceschini, Nora ^{[7
]}

Papanicolaou, George J. ^{[8
]}

Gibson, Quince ^{[9
]}

Yanek, Lisa R. ^{[10
]}

van der Harst, Pim ^{[11
]}

Ferguson, Jane F. ^{[12
]}

Crawford, Dana C. ^{[13
]}

Waite, Lindsay L. ^{[14
]}

Allison, Matthew A. ^{[1
]}

Criqui, Michael H. ^{[1
]}

McDermott, Mary M. ^{[15
]}

Mehra, Reena ^{[16
]}

Cupples, L. Adrienne ^{[17
]}

Hwang, Shih-Jen ^{[18
]}

Redline, Susan ^{[19
]}

Kaplan, Robert C. ^{[20
]}

Heiss, Gerardo ^{[7
]}

Rotter, Jerome I. ^{[21
]}

Boerwinkle, Eric ^{[22
]}

Taylor, Herman A. ^{[23
,24
]}

Eraso, Luis H. ^{[25
]}

Haun, Margot ^{[2
]}

Li, Mingyao ^{[26
]}

Meisinger, Christa ^{[27
]}

O'Connell, Jeffrey R. ^{[9
]}

Shuldineri, Alan R. ^{[9
,28
]}

Tybjaerg-Hansen, Anne ^{[29
]}

Frikke-Schmidt, Ruth ^{[29
]}

Kollerits, Barbara ^{[2
]}

Rantner, Barbara ^{[2
,30
]}

Dieplinger, Benjamin ^{[31
]}

Stadler, Marietta ^{[32
]}

Mueller, Thomas ^{[31
]}

Haltmayer, Meinhard ^{[31
]}

Klein-Weigel, Peter ^{[33
]}

Summerer, Monika ^{[2
]}

Wichmann, H. -Erich ^{[34
,35
,47
]}

Asselbergs, Folkert W. ^{[36
,37
,38
]}

Navis, Gerjan ^{[39
]}

Leach, Irene Mateo ^{[11
]}

Brown-Gentry, Kristin

Goodloe, Robert

Assimes, Themistocles L. ^{[40
]}

机构：

[1] Univ Calif San Diego, Dept Family & Prevent Med, Div Prevent Med, La Jolla, CA 92093 USA

[2] Innsbruck Med Univ, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, Innsbruck, Austria

[3] Baylor Coll Med, Dept Med, Cardiol Sect, Houston, TX 77030 USA

[4] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA

[5] Univ Michigan Hlth Care Syst, Deparment Internal Med, Div Cardiovasc Med, Ann Arbor, MI USA

[6] Univ Minnesota, Sch Publ Hlth, Dept Epidemiol & Community Hlth, Minneapolis, MN USA

[7] Univ N Carolina, Dept Epidemiol, Gillings Global Sch Publ Hlth, Chapel Hill, NC USA

[8] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA

[9] Univ Maryland, Sch Med, Dept Med, Div Endocrinol, Baltimore, MD 21201 USA

[10] Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD USA

[11] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands

[12] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA

[13] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA

[14] HudsonAlpha Inst Biotechnol, Huntsville, AL USA

[15] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA

[16] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA

[17] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[18] NHLBI, Framingham Heart Study, Ctr Populat Study, Framingham, MA USA

[19] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Sleep Med, Boston, MA 02115 USA

[20] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA

[21] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[22] Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol Human Genet & Environm Sci, Houston, TX USA

[23] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA

[24] Jackson State Univ, Jackson, MS USA

[25] Thomas Jefferson Univ Hosp, Jefferson Vasc Ctr, Philadelphia, PA 19107 USA

[26] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA

[27] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany

[28] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA

[29] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark

[30] Innsbruck Med Univ, Dept Vasc Surg, Innsbruck, Austria

[31] Konventhosp Barmherzige Brueder Linz, Dept Lab Med, Linz, Austria

[32] Hietzing Hosp, Med Dept Metab Dis & Nephrol 3, Vienna, Austria

[33] DRK Kliniken Berlin Mitte, Klin Innere Med Schwerpunkt Angiol, Berlin, Germany

[34] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany

[35] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[36] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands

[37] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands

[38] Univ Med Ctr, Dept Med Genet, Utrecht, Netherlands

[39] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands

[40] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

[41] Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, New York, NY USA

[42] Mt Sinai Sch Med, Marie Joseie & Henry R Kravis Ctr Cardiovasc Hlth, New York, NY USA

[43] Univ Penn, Div Cardiol, Vasc Med Sect, Perelman Sch Med, Philadelphia, PA 19104 USA

[44] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA

[45] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA

[46] Boston Univ, Sch Med, Dept Med, Sect Gen Internal Med, Boston, MA 02118 USA

[47] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany

[48] NHLBI, Framingham Heart Study, Boston, MA USA

来源：

ATHEROSCLEROSIS | 2012年 / 222卷 / 01期

基金：

美国国家卫生研究院;

关键词：

Ankle brachial index; Peripheral artery disease; Genetics; Candidate gene array; Meta-analysis; Ethnicity; PERIPHERAL ARTERIAL-DISEASE; GENOME-WIDE ASSOCIATION; RISK LOCI; APOLIPOPROTEIN(A) ISOFORMS; INSULIN-RESPONSE; FAMILY-HISTORY; SUSCEPTIBILITY; LIPOPROTEIN(A); POLYMORPHISMS; OUTPATIENTS;

D O I：

10.1016/j.atherosclerosis.2012.01.039

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 similar to 50,000 SNPs across similar to 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 x 10(-6) to denote statistical significance. Results: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (beta = -0.007, p = 6.02 x 10(-7)) and rs290481 in TCF7L2 (beta = -0.008, p = 7.01 x 10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p = 4.99 x 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 x 10(-3); rs290481, p = 8.88 x 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. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

引用

页码：138 / 147

页数：10

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