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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.

ABSTRACT: 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 (?=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (?=-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.

SUBMITTER: Wassel CL

PROVIDER: S-EPMC3596171 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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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.

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

Atherosclerosis 20120202 1

<h4>Background</h4>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.<h4>Methods and results</h4>We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ances ...[more]

PMID: 22361517

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Project description:BackgroundAnkle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) are both important indicators of arterial stiffness and vascular injury. At present, most studies on the relationship between ABI and baPWV and all-cause mortality in community-based elderly are analyzing ABI or baPWV alone, and will focus on a single special population such as diabetes and stroke. The purpose of this study was to evaluate the relationship between ABI and baPWV in a Chinese community-based elderly population, and to analyze their impact on all-cause mortality in a community-based population through a follow-up of nearly 10 years.MethodsParticipants were residents of the Wanshou Road community in Beijing, China. A total of 2,162 people in the community were included, with an average age of 71.48 years. During a mean follow-up period of 9.87 years, 1,826 subjects completed follow-up. Kaplan-Meier survival analysis and different Cox regression models were used to verify the association of ABI and baPWV with all-cause mortality. The selected subjects were divided into two groups according to ABI and baPWV, and ABI was divided into two groups with 0.90 as the cut-off point (group 1: 0.9 < ABI ≤ 1.3; group 2: ABI ≤ 0.9); according to the level of baPWV, they were divided into three groups (Tertile 1: baPWV <1761.5 cm/s; Tertile 2: 1761.5 ≤ baPWV <2121.5 cm/s; Tertile 3: baPWV ≥2121.5 cm/s).Results1,826 people were included in the statistical analysis, and the total mortality rate was 181.3/1000. The 10-year all-cause mortality rate of the abnormal ABI group (group 2) was 44.7%, and that of the normal ABI group (group 1) was 17.0%; The 10-year all-cause mortality rates from low to high in the baPWV tertile were 10.0%, 18.7%, and 26.4%. In the Cox proportional hazards model, after adjusting for possible confounders, the effect of baPWV on all-cause mortality was significant, with the 3rd tertile having a 1.647-fold higher risk of all-cause mortality than the 1st tertile (P = 0.014 ).ConclusionsABI and baPWV are risk factors affecting all-cause mortality in the elderly community population, and baPWV is an independent predictor of all-cause mortality in the elderly community population.

Dataset Information

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.

Publications

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.

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