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Friday 16 June 2006

Peroxisome proliferator activated receptor-α variant may predict fibrate response


A variant at the peroxisome proliferator activated receptor-α (PPARA) locus modulates the risk of cardiovascular (CV) events associated with insulin resistance and diabetes mellitus in men receiving fibrate treatment, findings from the VA-HIT study indicate.

Primary results from the Veterans Affairs High-Density Lipoprotein (HDL) Intervention Trial (VA-HIT) showed that gemfibrozil, which activates PPARA, significantly reduces CV events in men with established coronary heart disease and low HDL cholesterol levels (<40 mg/dl).

In a post hoc analysis, E Shyong Tai (Tufts University, Boston, Massachusetts) focused on 827 study participants who been genotyped for the L162V polymorphism at the PPARA locus. This is a functional variant that alters the transcriptional activation associated with fibrate therapy in vitro but has an unknown role in vivo.

The frequency of the V162 allele was 0.068, Tai and co-workers report in the journal Atherosclerosis, and only two individuals were homozygous for the V allele.

Relative to non-carriers, V162 carriers had significantly lower plasma levels of apolipoprotein A-I and HDL cholesterol, and were significantly more likely to have diabetes mellitus (37% vs 25%) or insulin resistance (42% vs 32%).

Importantly, Tai et al showed that in patients with diabetes or insulin resistance, treatment with gemfibrozil reduced CV events in non-carriers of the V162 allele (from 29.9% to 17.8%) as well as in carriers (from 14.7% to 4.8%).

Conversely, V162 allele carriers without diabetes or insulin resistance who were treated with gemfibrozil experienced significantly more CV events than those who received placebo (20.6% vs 13.6%, p=0.01).

"The effect of the L162V polymorphism at the PPARA locus on CV risk depends on the presence of diabetes mellitus/insulin resistance," Tai et al conclude.

"Although these data require confirmation in larger studies, they suggest that the PPARA L162V variant may be a potential marker for predicting which subjects will have a favorable response to fibrate therapy."

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