Annotated PGx Gene Information for HMGCR
Submitted by: Marisa Wong Medina (PARC)
Reviewed by: Issam Zineh (PEAR)
Submitted date: February 6, 2006
| Gene HGNC Name: | HMGCR |
|---|---|
| Gene Common Name: | HMG-CoA Reductase |
| Introductory Information: | The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase enzyme (EC 1.1.1.88) catalyzes the NADP-dependent conversion of HMG-CoA to mevalonate in the rate-limiting step of isoprenoid biosynthesis including cholesterol, haem A, ubiquinone, and dolichol. In addition, this pathway is also responsible for the production of prenylated proteins such as p21ras, which has a covalently linked farnesyl group [PMID: 1967820]. This glycoprotein is found both in the membrane of the endoplasmic reticulum and peroxisomal matrix, and is the target of the statin family of cholesterol lowering drugs. HMGCR is tightly regulated by transcriptional, post-transcriptional and post-translational mechanisms. The HMGCR gene is found on chromosome 5q13.3-q14 [PMID: 3866240] and is comprised of twenty exons spanning approximately 25 kilobases. The 4475 bp transcript encodes an 888 amino acid protein, and is widely expressed throughout the body. In the PRINCE trial of 1536 individuals treated with 40mg/day pravastatin for 24 weeks, Chasman et al. 2004 [PMID: 15199031] found a significant association between two common and tightly linked intronic SNPs (SNPs 12 A/T and 29 T/G) and reduced pravastatin efficacy as measured by smaller total cholesterol and LDL-cholesterol reductions. These two SNPs define haplotype 7 (H7), one of the ten major haplotypes identified in their predominantly Caucasian population. The association between SNP29 and LDL-cholesterol reduction with statin treatment was not replicated in the ACCESS trial, where Thompson et al. 2005 [PMID: 15199031] reported no significant association between SNP29 and LDL-cholesterol reduction in 293 genotyped Caucasian individuals treated with pravastatin. The trial also included 1902 individuals treated with atorvastatin, 477 individuals with fluvastatin, 476 individuals with lovastatin, and 468 individuals with simvastatin, and no other significant associations between SNP29 and statin efficacy were reported. |
| Key PubMed IDs: | 15199031, 1967820, 3866240, 3860301, 12535518, 16103896 |
| Key Pathways: | Statin Pathway |
| Drugs/Substrates: | pravastatin [PMID: 15199031, 16103896], atorvastatin, fluvastatin, lovastatin and simvastatin [PMID: 16103896] |
| Phenotypes/Diseases: | Variants associated with attenuated cholesterol reduction with pravastatin treatment [PMID: 15199031] |
| Important Variants: | HMGCR:SNP12, HMGCR:SNP29 |
| Important Haplotypes: | Pharmacogenetic study of statin therapy and cholesterol reduction. Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VP, Ridker PM. JAMA. 2004 June;291(23):2821-2827 [PMID: 15199031] |