The Effects Of Lipid Metabolism Related Gene Polyporphisms And DNA Methylation On The Baseline Lipid Levels And Lipid-lowering Efficacy Of Simvastatin

Backgrounds:The clinical studies indicate that dyslipidemia may promote atherosclerosis formation,leading to coronary heart disease(CHD),angina pectoris,acute myocardial infarction and other cardiovascular diseases,the relationship between dyslipidemia and cardiovascular disease(CVD)has been extremely clear.In recent years,the effects of genetics and epigenetics on dyslipidemia risk and lipid-lowering efficacy has become a tremendously hot topic.Objectives:(1)We conducted a cross-sectional study to investigate the effects of the ATP-binding cassette transporter 1(ABCA1)I883M and Lipoprotein lipase(LPL)HindⅢ polymorphisms on lipid levels in Chinese patients with primary hyperlipidemia.(2)The goal of our research was to evaluate whether CETP,LIPC and SREBF2 DNA methylations arerelated with baseline lipid profiles.And further identified whether the 3 genes DNA methylation levels influence the efficacy of simvastatin treatment in Chinese patients with primary hyperlipidemia.Methods:In total,we recruited 734 primary hyperlipidemia patients from Beijing and Anhui regions.(1)Of these,533 patients were available for this study.Serum lipid parameters and liver function(Aspartate aminotransferase,AST and Alanine aminotransferase,ALT)were determined by an automatic biochemistry analyzer,and low-density lipoprotein-cholesterol(LDL-C)was calculated by Friedewald’s equation.Genotyping of the ABCA1 I883M and LPL HindⅢ was actualized by the PCR-RFLP technique.(2)We used an extreme sampling approach by selecting individuals from the top and bottom 15%of lipid-lowering response residuals to simvastatin(n=104 in good response group and n =107 in bad response group)from all samples.And they were cured with simvastatin orally 20mg/d continuously for 8 weeks.Fasting serum lipids and liver function indexwere measured at baseline and after 56 days of treatment.211 hyperlipidemia patients were recruited for DNA methylation at the CETP,SREBF2 and LIPC gene using next generation sequencing.Results:(1)The frequency distribution of the ABCA1 I883M and LPL HindⅢpolymorphisms did not deviate from the Hardy-Weinberg equilibrium.Multivariate linear regression analysis showed that neither the ABCA1 1883M nor the LPL HindⅢpolymorphism was related to baseline serum lipid levels in the total population.However,among subjects with elevated Alanine aminotransferase(ALT)levels(ALT≥40U/L),carriers of the M allele of the ABCA1 gene had lower levels of high-density lipoprotein cholesterol(HDL-C)(P=0.001)and higher levels of low-density lipoprotein cholesterol(LDL-C)(P=0.001)after adjustment for age,sex,smoking,alcoholconsumption,education level,occupation,and work intensity.A test on interaction terms between the I833M polymorphism of ABCA1 gene and ALT on HDL-C and LDL-C levels also still significant(LDL-C:P=0.014;HDL-C:P=0.001).(2)We observed that high CETP DNA methylation levels were positively associated with elevated TG(r=0.318,p=0.002)in the good response group.DNA methylation levels at the SREBF2 gene locus was inversely associated with baseline HDL-C levels(r=-0.366,p=0.001)and the change in HDL-C(r=-0.315,p=0.008).There were significant associations between LIPC methylations and the lipid-Iowerling response(△HDL-C:r=-0.283,p=0.022,ATG:r=-0.183,p=0.044).Moreover,there were observationally interactions between DNA methylation levels and their polymorphisms on the efficacy of simvastatin.Conclusions:(1)There are significant interactive effects between ABCA1 I883M and ALT levels on HDL-C and LDL-C levels.However,the LPL HindⅢ polymorphism did not influence lipid levels.(2)Our results suggest that the DNA methylation levels inthe CETP and SREBF2 gene are associated with baseline lipid levels.And epipolymorphisms in both the SREBF2 and CETP are associated with lipid-lowering therapy of simvastatin in Chinese hyperlipidemia patients.