Pharmacogenetics, the tailoring of drug treatment according to individual
genotype, has been widely proclaimed as a first step toward personalized medicine.
In this issue of THE JOURNAL, Chasman et al1 report
the association of 2 common polymorphisms in the 3-hydroxy-3-methylglutaryl-CoA
reductase (HMGCR) gene with reduced efficacy of pravastatin
therapy. In a survey of 148 single nucleotide polymorphisms in 10 genes involved
in lipid metabolism, carriers of 2 linked SNPs in the HMGCR gene showed significantly smaller reductions in levels of cholesterol,
triglycerides, and low-density lipoprotein cholesterol with treatment. Statins,
the most potent and widely used cholesterol-lowering drugs, function as competitive
inhibitors of HMGCR, the rate-limiting enzyme for cholesterol synthesis. This
study is the first to demonstrate the impact of genetic variation in the HMGCR
drug target for this popular class of drugs, justifying the need for further
study to validate and perhaps translate these findings into the clinical setting.
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