Annotated PGx Gene Information for HMGCR

Citation: PharmGKB: very important pharmacogene - HMGCR. Medina MW, Sangkuhl K, Klein TE, Altman RB.
Pharmacogenet Genomics. ePub ahead of print January 15 2010. PMID: 20084049

PharmGKB VIP Submitted by: Marisa Wong Medina (PARC), Katrin Sangkuhl (PharmGKB)
PharmGKB Submission date: February 6, 2006
PharmGKB VIP Updated: December 18, 2009
PharmGKB VIP Reviewed: December 18, 2009

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 [PMID: 1967820]. The inhibition of these small GTP-binding proteins is thought to mediate the pleiotropic effects of statins [PMID: 18068482]. Given its importance in regulating mevalonate production for both sterol and non-sterol end-products, HMGCR is very tightly regulated by transcriptional, post-transcriptional and post-translational mechanisms [PMID: 1967820]. 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, 18802019, 18559695]. In the Pravastatin Inflammation/CRP Evaluation (PRINCE) trial of 1536 individuals treated with 40mg/day pravastatin for 24 weeks, Chasman et al. 2004 [PMID: 15199031] reported 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 this predominantly Caucasian population. H7 was later redefined by Krauss et al. [PMID: 18332269], who discovered that the H7 haplotype includes an additional intronic SNP, rs3846662, otherwise known as SNP 20144, thus defining the H7 haplotype as carriers of SNPs 12, 29 and 20144 [PMID: 18332269]. In addition to the original observation in the PRINCE population, the association between H7 and statin response has also been reported in two additional independent populations, The Cholesterol and Pharmacogenomics (CAP) and the Genetics of Diabetes Audit and Research in Tayside Scotland Database (GoDARTS); however, this association failed to replicate in the Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS), Assessment of Lescol in Renal Transplantation (ALERT), Prospective Study of Pravastatin in the Elderly at Risk (PROPSER), or Treatment to New Targets (TNT) studies [PMID: 18332269, 18815589, 16103896, 17563401, 18261733]. Recently, alternative splicing of exon 13 of the HMGCR transcript, HMGCR13( - ), has been identified as marker of statin response as its expression is correlated with the magnitude of plasma total cholesterol, LDL-cholesterol, apolipoprotein (apo) B and triglyceride reductions with statin treatment [PMID: 18559695]. Since SNP 20144 has been shown to directly influence production of the HMGCR13( - ) transcript [PMID: 18802019, 18559695], HMGCR alternative splicing is likely one of the molecular mechanisms contributing to the association between H7, H2 and statin response. Despite the failure to replicate in several populations, the identification of an association between H7 and statin response in three independent populations, together with molecular data of a functional effect of the HMGCR H7 haplotype provides strong evidence that this genotypic relationship with statin response is valid.
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

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