Annotated PGx Gene Information for HMGCR
Submitted by: Marisa Wong Medina (PARC) Submitted date: February 6, 2006
Reviewed by: Issam Zineh (PEAR) Reviewed date: 2006
Updated by: Marisa Wong Medina (PARC) Updated date: December 19, 2008
| 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 cholesterol biosynthesis, and is the target of the statin family of cholesterol lowering drugs. In addition, this pathway also produces isoprenoid intermediates, which act as lipid attachments for intracellular signaling molecules such as Rho, Ras and Rac. The inhibition of these small GTP-binding proteins is thought to mediate the pleiotropic effects of statins [PMID: 18068482]. HMGCR is a glycoprotein found both in the membrane of the endoplasmic reticulum and peroxisomal matrix, and is highly 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 which is widely expressed throughout the body. Alternative splicing of exon 13 has been described, but it is unknown if this variant is translated into a protein [PMID: 14684825]. 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 SNP 12 or 29 and statin response has also been reported in two independent populations, CAP and GoDARTS; however, this association was not found in the ACCESS, ALERT or PROPSER studies [PMID: 18332269, 18815589, 16103896, 17563401, 18261733]. With additional resequencing and genotyping of tagSNPs spanning the entire HMGCR gene, Krauss et al. found that the H7 haplotype includes an additional intronic SNP, rs3846662, otherwise known as SNP 20144, thus redefining the H7 haplotype as carriers of SNPs 12, 29 and 20144 [PMID: 18332269]. SNP 20144 was also identified in another haplotype H2, and in the CAP population, African American carriers of either the H7 or H2 haplotypes had significantly lower LDL-cholesterol response to simvastatin (40mg/day, 6 weeks), compared to individuals who did not carry either H7 or H2 (-36.9% versus -40.6% respectively). Additionally, individuals who had both H2 and H7 had the lowest percent LDL-cholesterol response than either H2 or H7 carrier alone [PMID: 18332269]. Alternative splicing of exon 13 of the HMGCR transcript (HMGCRv_1) is thought to be one of the molecular mechanisms underlying the association between H7 and H2, and statin response. SNP 20144 has been shown to directly influence production of the HMGCRv_1 transcript, whose expression is correlated with the magnitude of plasma total cholesterol, LDL cholesterol, apoB and triglyceride reductions with statin treatment [PMID: 18559695]. |
| Key PubMed IDs: | 15199031, 3866240, 3860301, 14684825, 18332269, 18815589, 17563401, 18261733, 18559695, 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, HMGCR:SNP20144 |
| 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], HMGCR:H2, HMGCR:H7 |