A paucimorphic variant in the HMG-CoA reductase gene is associated with lipid-lowering response to statin treatment in diabetes: a GoDARTS study

Abstract

Background: Considerable interindividual variation exists in cholesterol-lowering response to 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors (statins). HMGCR catalyzes the rate-limiting step in cholesterol biosynthesis, and also plays a significant role in cholesterol homeostasis. We evaluated the association of a single nucleotide polymorphism (rs17238540) in the HMGCR gene with lipid-lowering response to statins in a large population-based cohort of patients with diabetes.

Methods: One thousand six hundred and one patients commencing statins between 1993 and 2006 were identified from the Genetics of Diabetes Audit and Research in Tayside Scotland database. Statin response was determined by both percentage change in lipids, and whether patients failed to reach a total cholesterol target of less than or equal to 4 mmol/l. Covariates included HMGCR genotype, baseline lipids, age, sex, adherence and statin dose. All patients were genotyped for rs17238540 using a TAQMAN-based allelic discrimination assay.

Results: Twenty-eight percent of individuals homozygous for the more frequent T allele failed to reach target compared with 51% of the individuals with a single copy of the minor G allele (carrier frequency 3.3%), with an adjusted odds ratio (95% confidence interval) for failure of 2.93 (1.61-5.34) mmol/l, P = 0.0005. In addition, we found that the heterozygotes had a 13% smaller reduction in total cholesterol (-32.3 vs. -37.1%, P = 0.0081) and a 27% smaller reduction in triglycerides (-27.5 vs. -37.6%, P = 0.0046).

Conclusion: Individuals heterozygous for the G allele of rs17238540 in the HMGCR gene may respond less well to statin therapy in terms of total cholesterol and triglyceride lowering.