Peroxisome proliferator-activated receptor-delta genotype influences metabolic phenotype and may influence lipid response to statin therapy in humans: a genetics of diabetes audit and research Tayside study.

CONTEXT: Previous studies have identified a single-nucleotide polymorphism in the gene encoding peroxisome proliferator-activated receptor-delta (PPARD), rs2016520, that is associated with changes in metabolic disease in some but not all studies, which suggests that PPARD agonists may have therapeutic benefits for the treatment of metabolic disorders, including dyslipidemia, type 2 diabetes, and obesity. OBJECTIVE: The objective of the study was to determine whether rs2016520 or other single-nucleotide polymorphism in the PPARD locus influenced the risk of developing various characteristics of metabolic disease. DESIGN: Haplotype tagging analysis across PPARD was performed in 11,074 individuals from the Welcome Trust U.K. Type 2 Diabetes Case Control Collection. RESULTS: In subjects with and without type 2 diabetes, rs2016520 was associated with body mass index, high-density lipoprotein cholesterol, leptin, and TNFalpha and was dependent on gender. CONCLUSION: The current results suggest differential effects of PPARdelta in males and females.

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

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.

Apolipoprotein E genotypes are associated with lipid-lowering responses to statin treatment in diabetes: a Go-DARTS study.

BACKGROUND: Apolipoprotein E (APOE) genotypes have been associated with variations in plasma-lipid levels and with response to statins, although the influence of APOE on the response to statins remains controversial, especially in patients with diabetes. We sought to evaluate the association of the APOE genotype with the low-density lipoprotein cholesterol (LDLc)-lowering response to statins, in a large population-based cohort of patients with diabetes. METHODS AND RESULTS: A total of 1383 patients, commencing statins between 1990 and 2006, were identified from the Genetics of Diabetes Audit and Research in Tayside Scotland database. Statin response was determined both by the minimum LDLc achieved, and by the failure of the patients to reach a clinical target LDLc (< or =2 mmol/l). APOE genotype and potential confounding covariates were entered into the linear and logistic regression models. RESULTS: We found an association of APOE genotypes with both baseline and treatment responses. E2 homozygotes achieved lower LDLc levels (mean 0.6; confidence interval: 0.1-1.1 mmol/l) than E4 homozygotes (mean 1.7; confidence interval: 1.4-1.9 mmol/l; P=2.96 x 10). Minimum LDLc was associated by a linear trend with genotype. This relationship remained statistically significant after adjustment for baseline LDLc, adherence, duration, dose, smoking, and age. None of the E2 homozygotes failed to reach the target LDLc, compared with 32% of the E4 homozygotes (P=5.3 x 10). CONCLUSION: This study demonstrates the potential clinical value of the APOE genotype as a robust marker for LDLc responses to statin drugs, which might contribute to the identification of a particularly drug-resistant subgroup of patients. This marker provides information over and above baseline lipid levels.