The L162V polymorphism at the peroxisome proliferator activated receptor alpha locus modulates the risk of cardiovascular events associated with insulin resistance and diabetes mellitus: The Veterans Affairs HDL Intervention Trial (VA-HIT)

E. Shyong Tai, Dorothea Collins, Sander J. Robins, John J. O'Connor, Hanna E. Bloomfield, Jose M. Ordovas, Ernst J. Schaefer, Margaret E. Brousseau

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Background: The Veterans Affairs HDL Intervention Trial (VA-HIT) showed that gemfibrozil, which activates peroxisome proliferator-activator receptor α (PPARα), significantly reduced the risk of cardiovascular (CV) events in men with low HDL cholesterol (<40 mg/dl) and established coronary heart disease. Treatment was particularly beneficial in those with insulin resistance (IR) or diabetes mellitus (DM). We hypothesized that the association between a functional polymorphism at the PPARA locus (L162V) and the risk of a CV event, as well as response to fibrate therapy, might be greatest in those with either IR or DM (DM/IR) in VA-HIT. Methods and results: A total of 827 men (placebo, n = 413; gemfibrozil, n = 414) from the VA-HIT were genotyped. This population included a high proportion of subjects with DM/IR. In VA-HIT, the PPARA V162 allele was associated with reduced levels of HDL cholesterol and the presence of DM/IR at baseline. It was also associated with reduced risk of CV events in those with DM/IR but not in those with neither (DM/IR *PPARA genotype, P = 0.005). Among subjects with DM/IR, treatment with gemfibrozil reduced CV events in non-carriers from 29.9 to 17.8% and carriers of the V162 allele from 14.7 to 4.8%. In contrast, carriers of the V162 allele with no DM/IR who were treated with gemfibrozil experienced significantly more CV events than did those who received placebo (20.6% versus 13.6%; P = 0.01). Conclusions: The effect of the L162V polymorphism at the PPARA locus on CV risk depends on the presence of DM/IR. Among subjects treated with gemfibrozil, the V162 allele was associated not only with reduced CV risk in subjects with DM/IR, but also with significantly increased CV risk in the absence of these traits, identifying this genetic variant as a potential marker for predicting which subjects may have a favorable response to fibrate therapy.

Original languageEnglish (US)
Pages (from-to)153-160
Number of pages8
JournalAtherosclerosis
Volume187
Issue number1
DOIs
StatePublished - Jul 2006

Bibliographical note

Funding Information:
This study was funded by grant R01 HL-60935 from the National Institutes of Health, by contract 53-19550-50-003 from the US Department of Agriculture Research Service, and by the Cooperative Studies Program of the Department of Veterans Affairs of the Clinical Science Research and Development Service.

Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.

Keywords

  • Fibrate
  • HDL
  • Insulin resistance
  • PPARA
  • Polymorphism

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