Study On The Association Of LEP G2548A And LEPR Q223R Polymorphisms With Statin-induced CK Elevation And Metabolic Risks

Hyperlipidemia, a common metabolic disease, is one of the most important risk factors of the cardiovascular and cerebrovascular diseases. And it is closely related to atherosclerosis, kidney disease, diabetes, obesity, fatty liver, especially associated with hypertension and cardio-cerebro vascular disease, which cause serious harm to people’s health. Statins are the most widely used lipid-lowering drugs in clinical practice. However, because of individual differences induced by genetic and environmental factors, the lipid-lowering effect of statins among individuals also exhibited considerable variation. Meanwhile, statins have certain side effects.Objectives:(1) To investigate whether LEP G2548A and LEPR Q223R polymorphisms influence serum lipid levels and whether the two polymorphisms affect the efficacy of simvastatin treatment in Chinese patients with primary hyperlipidemia. (2) To investigate the association of LEP G2548A and LEPR Q223R polymorphisms with statin-induced CK elevation and metabolic risks, such as hyperlipidemia, obesity and hyperglycemia among Chinese patients with hyperlipidemia.Methods:Totally 734 patients with primary hyperlipidemia were recruited for the study from Beijing and Anhui, China. In this study, (1) We used an extreme-sampling approach by selecting 212 individuals from the top and bottom 15% of adjusted lipid-lowering response residuals to simvastatin (n=106 in each group of good or bad response) from a total of 734 samples with primary hyperlipidemia. (2) We enrolled 587 individuals from a total of 734 samples with hyperlipidemia. They were treated with simvastatin orally 20 mg/d. Fasting serum lipids, fasting glucose, creatine kinase and other parameters were measured at baseline and after 4 and 8 weeks of simvastatin treatment. Genotyping of LEP G2548A and LEPR Q223R was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).Results:(1) More patients in the good response group (27%) had LEPR Q223R than in the bad response group (16%, P=0.046). Secondary stratified analyses showed that patients carrying the RR genotype of the LEPR Q223R gene had significantly higher HDL-C levels than those with the QR genotype at baseline (P=0.034) among good responders. After 29 consecutive days of treatment with simvastatin, patients carrying the RR genotype had a significantly larger decrease in TG (change:-0.74±0.92, P=0.036) and TC levels (change:-1.77±0.68, P=0.023) compared with those carrying QR genotype among bad responders. After Bonferroni correction, the results were not statistically significant. (2) Further multiple regression analyses showed that patients carrying the QQ genotype of the LEPR Q223R gene had significantly higher BMI than those with the QR (P=0.033) and RR (P=0.029) genotype, along with higher fasting glucose levels than RR genotype (P=0.036). Patients carrying AA genotype of LEP G2548A gene had significantly higher baseline creatine kinase levels than those with GG genotype (P=0.043). Patients carrying the AA genotype had a significantly larger elevation in CK levels compared with those carrying GA genotype after 29 (P=0.005) and 57 (P<0.001) consecutive days of simvastatin treatment. Carriers of GG genotype had significantly higher baseline TC levels than AA (P=0.016), along with a larger reduction of HDL-C levels (P=0.040) after 57 days’simvastatin treatment.Conclusions:(1) LEPR Q223R polymorphism could modulate the efficacy of simvastatin treatment in lipid levels among Chinese patients with primary hyperlipidemia. (2) LEP G2548A polymorphism could effectively improve the side effect of statin-induced CK elevation, and modulate the efficacy of simvastatin treatment in Chinese patients with hyperlipidemia.