The effect of ABCA1 gene DNA methylation on blood pressure levels in a Chinese hyperlipidemic population.

Hypertension is an important public health challenge worldwide. Epigenetic studies are providing novel insight into the underlying mechanisms of hypertension. We investigated the effect of DNA methylation in ATP-binding cassette transporter 1 (ABCA1) gene on blood pressure levels in a Chinese hyperlipidemic population. We randomly selected 211 individuals with hyperlipidemia who had not received any lipid-lowering treatment at baseline from our previous statin pharmacogenetics study (n = 734). DNA methylation loci at the ABCA1 gene were measured by MethylTarget, a next generation bisulfite sequencing-based multiple targeted cytosine-guanine dinucleotide methylation analysis method. Mean DNA methylation level was used in statistical analysis. In all subjects, higher mean ABCA1_B methylation was positively associated with systolic blood pressure (SBP) (ß = 8.27, P = 0.008; ß = 8.78, P = 0.005) and explained 2.7% and 5.8% of SBP variation before and after adjustment for lipids, respectively. We further divided all patients into three groups based on the tertile of body mass index (BMI) distribution. In the middle tertile of BMI, there was a significantly positive relationship between mean ABCA1_A methylation and SBP (ß = 0.89, P = 0.003) and DBP (ß = 0.32, P = 0.030). Mean ABCA1_A methylation explained 11.0% of SBP variation and 5.3% of DBP variation, respectively. Furthermore, mean ABCA1_A methylation (ß = 0.79; P = 0.007) together with age and gender explained up to 24.1% of SBP variation. Our study provides new evidence that the ABCA1 DNA methylation profile is associated with blood pressure levels, which highlights that DNA methylation might be a significant molecular mechanism involved in the pathophysiological process of hypertension.

Effect of ABCG1 gene DNA methylations on the lipid-lowering efficacy of simvastatin.

Aim: We investigated the effect of ABCG1 gene DNA methylation in the lipid-lowering efficacy of simvastatin. Materials & methods: An extreme sampling approach was used to select 211 individuals from the top and bottom 15% of adjusted lipid-lowering response residuals to simvastatin after eight consecutive weeks. DNA methylation was measured before treatment by the MethylTarget bisulfite sequencing method. Results:ABCG1_A DNA methylations were negatively associated with baseline high-density lipoprotein cholesterol (HDL-C) and the change in HDL-C after treatment. ABCG1_C methylations were also related to the change in triglyceride and HDL-C. Moreover, mean ABCG1_A and ABCG1_C methylations explain 7.2% of the ΔTC (total cholesterol) and 17.5% of the ΔHDL-C level variability, respectively. Conclusion: DNA methylations at the ABCG1 gene play significant inhibitory effects in the lipid-lowering therapy of simvastatin.

PHOSPHO1 Gene DNA Methylations are Associated with a Change in HDL-C Response to Simvastatin Treatment.

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 (ß=-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 (ß=-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.