Juanlin Fan, Qianru Cai, Di Zhang, Justin Weinstock, Xiaoxiao Qu and Shanqun Jiang* Pages 4944 - 4952 ( 9 )
Objective: Our aim was to detect the effects of DNA methylations in the phosphoethanolamine/ phosphocholine phosphatase (PHOSPHO1) gene on the therapeutic efficacy of simvastatin.Methods: We used an extreme sampling approach by selecting 211 individuals from approximately the top and bottom 15% of adjusted lipid-lowering response residuals to simvastatin (n=104 for the high response group and n=107 for the low response group) from a total of 734 subjects with hyperlipidemia. They received a daily oral dose of 20 mg simvastatin for eight consecutive weeks. DNA methylation loci at the PHOSPHO1 gene were measured using high-throughput next-generation sequencing-based sequencing technology. Fasting serum lipids were measured at baseline and after eight weeks of simvastatin treatment. Results: Mean PHOSPHO1 DNA methylation had a significant negative correlation with high-density lipoprotein cholesterol (HDL-C) variation (β=-0.014, P=0.045) in the high response group. After stratifying by body mass index (BMI), the associations between the PHOSPHO1 DNA methylations and the change in HDL-C in response to simvastatin were more significant in obese subjects with a BMI of 25 kg/m2 or higher (β=-0.027, P=0.002). Mean PHOSPHO1 methylation and traditional predictors could explain up to 24.7% (adjusted R2) of the change in HDL-C response in obese patients. There was a statistically significant additive interaction term (P=0.028) between BMI and mean PHOSPHO1 methylation in the model of the change in HDL-C in response to simvastatin. Conclusion: Our findings suggest that PHOSPHO1 DNA methylations are associated with a change in HDL-C in response to simvastatin treatment, and this association is especially dependent on the extent of patient obesity.
PHOSPHO1, DNA methylation, Hyperlipidemia, Simvastatin, lipoprotein, phosphocholine.
School of Life Sciences, Anhui University, Hefei, School of Life Sciences, Anhui University, Hefei, School of Life Sciences, Anhui University, Hefei, Department of Statistics, University of Virginia, Charlottesville, VA, Center for Genetics & Genomics Analysis, Genesky Biotechnologies Inc., Shanghai, School of Life Sciences, Anhui University, Hefei