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).
BACKGROUND
The Veterans Affairs HDL Intervention Trial (VA-HIT) showed that gemfibrozil, which activates peroxisome proliferator-activator receptor alpha (PPARalpha), 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.


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.
Tai
E Shyong
ES
Nutrition and Genomics Unit, Jean Mayer USDA Human Nutrition Research Center for Aging at Tufts University, Boston, MA, USA.
Collins
Dorothea
D
Robins
Sander J
SJ
O'Connor
John J
JJ
Bloomfield
Hanna E
HE
Ordovas
Jose M
JM
Schaefer
Ernst J
EJ
Brousseau
Margaret E
ME
D000483:Alleles; D002318:Cardiovascular Diseases / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D048909:Diabetes Complications / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism*; D015248:Gemfibrozil / Q000494:pharmacology; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007333:Insulin Resistance; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008297:Male; D047493:PPAR alpha / Q000235:genetics*; D010919:Placebos; D011110:Polymorphism, Genetic
D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; D047493:PPAR alpha; D010919:Placebos; D015248:Gemfibrozil