Abstract
BackgroundGP78 is a membrane-anchored ubiquitin ligase mediating the degradation of 3-hydroxy-3-methyl-glutaryl-CoA coenzyme A reductase (HMGCR) and Insig-1, which was very essential for the synthesis of cholesterol process. Cholesterol levels have a causal role in the development of cardiovascular disease. The aim of the present study was to assess the association between the human gp78 gene polymorphism and coronary artery disease (CAD) in a Han and Uygur population of China.MethodsWe used two independent case–control studies: a Han population (602 CAD patients and 572control subjects) and a Uygur population (374 CAD patients and 376control subjects). All CAD patients and controls were genotyped for the same three single nucleotide polymorphisms (SNPs) (rs731119, rs2617849and rs2440472) of gp78 gene by a Real-time PCR instrument.ResultsIn the Han population, for total and men, the distribution of SNP3 (rs2440472) alleles and the dominant model (AA vs AG + GG) and recessive model (GG vs AG + AA) showed a significant difference between CAD and control participants (for allele: P = 0.003 and P = 0.002, respectively; for dominant model: P = 0.041 and P = 0.026, respectively; for recessive model: p = 0.004 and p = 0.004, respectively).The significant difference in both the two models was retained after adjustment for covariates (for dominant model OR:0.760, 95% confidence interval [CI]:0.584-0.99, P = 0.042; OR:0.686, 95% CI: 0.498-0.946, P = 0.022, respectively; for recessive model OR: 1.451, 95% CI: 1.067-1.974, P = 0.018; OR: 1.789, 95% CI: 1.219-2.627, P = 0.000). Our data was also assessed via haplotype-based case–control studies. For the Han population, for total, The G-T-G haplotype in CAD was significantly higher than that in the control group (P = 0.02), and the G-C-A haplotype in CAD was significantly lower than that in the control group (P = 0.0443), And for man, the G-T-G haplotype in CAD was significantly higher than that in the control group (P = 0.0048).ConclusionsThe GG genotype and G allele of rs2440472 in gp78 gene could be a risk genetic marker of CAD in Han population in China.
Highlights
The etiology and pathogenesis of coronary artery disease (CAD) are likely to comprise a multifactorial disorder resulting from inheritance of several susceptibility genes, as well as multiple environmental determinants [1,2]
A high level of sterol promotes the interaction between hydroxy-3-methylglutaryl-CoA coenzyme A reductase (HMGCR) and Insig-1/-2, which causes the ubiquitination of HMGCR by gp78 and subsequent degradation [11]
For Han and Uygur population, there was no significant difference in age between CAD patients and control subjects it means the study was age-matched case–control study
Summary
The etiology and pathogenesis of coronary artery disease (CAD) are likely to comprise a multifactorial disorder resulting from inheritance of several susceptibility genes, as well as multiple environmental determinants [1,2]. Sterol promotes the degradation of HMGCR through the ubiquitin-proteasome pathway, and slows down cholesterol biosynthesis [9]. When the cholesterol level is low, HMGCR is kept apart from the Insig-gp complex and stabilized. A high level of sterol promotes the interaction between HMGCR and Insig-1/-2, which causes the ubiquitination of HMGCR by gp and subsequent degradation [11]. Besides HMGCR, gp mediates the degradation of Insig-1 protein. GP78 is a membrane-anchored ubiquitin ligase mediating the degradation of 3-hydroxy-3-methylglutaryl-CoA coenzyme A reductase (HMGCR) and Insig-1, which was very essential for the synthesis of cholesterol process. The aim of the present study was to assess the association between the human gp gene polymorphism and coronary artery disease (CAD) in a Han and Uygur population of China
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