A 17 Basepair Indel Variant In HMGCR 3'UTR Associated With Plasma Lipid Levels And Susceptibility To Coronary Heart Disease And Prognosis Of Chronic Heart Failure

Objectives:Dyslipidemia is a crucial risk factor for cardiovascular disease.Recent genome-wide association studies have identified hundreds of loci associated with plasma lipid levels and risk of cardiovascular disease.However,most of the studies were focused on the gene-coding region,genetic variants in the non-coding region were not adequately investigated.In this study,we resequenced the HMGCR gene,a key enzyme of cholesterol synthesis,and investigated the effect of the genetic variants on plasma lipid levels and the risk of coronary heart disease?CHD?and prognosis of heart failure?HF?.Methods:The 20 exons of HMGCR were resequenced in 48 randomly selected health controls subjects.Identified common variants were further screened in 800 control subjects and 1000 CHD patients.The putative functional variant rs150429867 was subsequently genotyped in a second CHD case-control cohort.Furthermore,2986 HF patients were continuouslly enrolled in this study and underwent a mean follow-up of 20.4 months.The17 bp indel variant rs150429867 was also genotyped in the HF population.Association of this variant with the prognosis of heart failure was analysised.Finally,mechanistic experiments were performed to investigated the influence of rs150429867 on the gene expression.Results:Through re-sequencing,4 common variant were identified?minor allele frequecy>0.01?.The 17bp indel variant rs150429867 in the 3'untranslational region of HMGCR was associated with elevated plasma lipid levels.Furthermore,rs150429867variant was associated with the susceptibility of CHD in the case-control study?odds ratio:1.15,95%CI:1.06-1.35,p=0.021?,which was replicated in the second CHD case-control cohort?odds ratio:1.08,95%CI:1.03-1.22,p=0.041?.The HF follow-up study confirmed that statin use was significantly associated with decreased risk of cardiovascular death and heart transplantation(hazard ratio:0.51,95%CI:0.40-0.64,p=5.96×10^-9).Subgroup analysis revealed that rs150429867 genotype was associated with the prognosis of heart failure in no-statin HF patients?hazard ratio:0.13,95%CI:0.02–0.90,p=0.039?.Cell experiments demonstrated that rs150429867 mutant allele could significantly increase the HMGCR 3'UTR luciferase activity.Conclusions:Genetic variant rs150429867 in the 3'UTR of HMGCR was associated with plasma lipid levels and susceptibility to CHD.HMGCR inhibitors?statins?could significantly reduce risk of adverse events in HF patients.The rs150429867 mutant allele homozygotes showed favourable prognosis of heart failure in no-statin HF patients.Further more,rs15029867 variant could also influence the HMGCR 3'UTR luciferase activity.