High-Risk Polymorphisms Associated with the Molecular Function of Human HMGCR Gene Infer the Impedance of Cholesterol Biosynthesis

Abstract

Background: HMG-CoA reductase or HMGCR (3-Hydroxy-3-methylglutaryl-CoA reductase) is a rate-limiting enzyme involved in cholesterol biosynthesis. HMGCR plays an important role in the possible occurrence of hypercholesterolemia leading to atherosclerosis and coronary heart disease. This enzyme is a major target for cholesterol lowering drugs such as “statins” which blocks the synthesis of mevalonate, a precursor for cholesterol biosynthesis. This study aims to characterize deleterious mutations and classify functional Single Nucleotide Polymorphisms (SNPs) of the HMGCR gene through analysis of functional and structural evaluation, domain association, solvent accessibility, and energy minimization studies. Results: Among 6,815 SNP entries from different databases, approximately 388 SNPs were found to be missense. Analysis showed that seven missense SNPs are more likely to have deleterious effects. A tertiary model of the mutant protein was constructed to determine the functional and structural effects of the HMGCR mutation. In addition, the location of the mutations suggests that they may have deleterious effects because most of the mutations are resides in the functional domain of the protein. The findings from the bunch of bioinformatics tools predicted that rs147043821 and rs193026499 missense SNPs could cause significant structural and functional instability in the mutated proteins of the HMGCR gene. Conclusion: Therefore, the results of the current study would undoubtedly be accommodating in future endeavors concerning drug discovery and therapeutics against hypercholesterolemia.