ABSTRACT
Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.
Subject(s)
Blood Glucose/drug effects , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Membrane Transport Proteins/genetics , Metformin/therapeutic use , Pharmacogenomic Variants , Polymorphism, Single Nucleotide , Aged , Aged, 80 and over , Biomarkers/blood , Blood Glucose/metabolism , Databases, Factual , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/genetics , Female , Genotype , Glycated Hemoglobin/metabolism , Humans , Male , Membrane Transport Proteins/metabolism , Middle Aged , Octamer Transcription Factor-1/genetics , Octamer Transcription Factor-1/metabolism , Organic Cation Transport Proteins/genetics , Organic Cation Transport Proteins/metabolism , Organic Cation Transporter 2 , Phenotype , Symporters , Treatment OutcomeABSTRACT
The objective of this study was to investigate whether common variation in genes involved in lipid metabolism modify the effect of statins on serum total cholesterol concentration. Statin users were identified in the Rotterdam Study, a prospective population-based cohort study of subjects >55 years of age. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in lipid metabolism and total cholesterol response to statin therapy, using linear regression analysis and adjusting for potential confounders. Replication was performed in an independent extended cohort of the Rotterdam Study. Genotype data and total cholesterol concentrations after start of statin therapy were available for 554 newly started statin users. Two SNPs were associated with a significantly higher cholesterol concentration under statin therapy: SNP rs1532624 in the CETP gene (ß: 0.141 mmol l(-1), P=0.004 per additional allele) and SNP rs533556 in the APOA1 gene (ß: 0.138 mmol l(-1), P=0.005 per additional allele). In the replication sample, only the CETP rs1532624 SNP again showed a significant association. The SNPs were not related to baseline total cholesterol in non-statin users. In conclusion, we found that the CETP rs1532624 polymorphism is associated with cholesterol response to statin therapy in a cohort of elderly subjects in the general population.