|
Title Community Sourced Discovery of Genetic Variants in Statin Metabolism |
|
Type Free Paper Session 1 |
|
Theme ACC Asia & SCS 32nd Annual Scientific Meeting |
|
Topic Heart Failure / Cardiovascular Rehabilitation & Preventive Cardiology |
|
Main Author Wei Loong Sherman Yee1 |
|
Presenting Author Wei Loong Sherman Yee1 |
|
Co-Author Chester Drum1 |
|
Department / Institution / Country Medicine / National University of Singapore / Singapore1 |
|
Objective(s) 1) Evaluate the inter-individual variability in statin drug metabolism using statin drug and drug metabolite concentrations obtained during late elimination phase in the Singapore population 2) Assess the association between clinical and pharmacogenetic variables and statin drug and metabolite concentrations in subjects |
|
Material and Method 1500 subjects on atorvastatin and simvastatin will be prospectively recruited at two outpatient heart clinics, with each clinic contributing half of the study population. Two blood draws, three hours apart, are done per patient per visit via venipuncture. Blood drawn is used for genomic analysis then spun down to plasma for clinical biomarker measurements via COBAS c111 and drug and metabolite measurements via LC-MS/MS. |
|
Result(s) The first 100 atorvastatin subjects were analyzed. Intra-individual variation of drug and metabolite concentrations ranged from 8% to 30% while inter-individual variation ranged from 70% to 100% for different metabolites. Non-parametric tests were used to test for significant differences between categories. There were significant differences (p<0.05) in drug concentrations found between different orally administered doses, with higher doses showing higher plasma concentrations. This was true for atorvastatin metabolites as well. In addition, there was a significant difference (p<0.05) in atorvastatin concentration between the SLCO1B1 rs4149046 genotypes. No difference was observed for other atorvastatin metabolite concentrations. Spearman rank correlation was used to analyze associations between quantitative variables. Significant correlations (p<0.05) were seen between urea, creatine kinase and triglycerides with atorvastatin and metabolite concentrations. Significant correlations were also seen between hsCRP and the metabolite:parent drug ratios. Simple linear regression was used to judge the contribution of genetic variables to statin drug and metabolite concentration. |
|
Conclusion Statin drug and drug metabolite levels obtained during the late elimination phase have been found to be significantly associated with known pharmacogenomic variants of statin metabolism. They were also significantly correlated with other clinical biomarkers. |