PharmGKB

Abstract

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 [1]. The inhibition of these small GTP-binding proteins is thought to mediate the pleiotropic effects of statins [2]. Given its importance in regulating mevalonate production for both sterol and nonsterol end products, HMGCR is very tightly regulated by transcriptional, posttranscriptional, and posttranslational mechanisms [1]. The HMGCR gene is found on chromosome 5q13.3-q14 [3] and is comprised of 20 exons spanning approximately 25 kb. 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 whether this variant is translated into a protein [4–6]. In the Pravastatin Inflammation/CRP Evaluation (PRINCE) trial of 1536 individuals treated with 40 mg/day pravastatin for 24 weeks, Chasman et al. [7] reported a significant association between two common and tightly linked intronic single nucleotide polymorphisms (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 10 major haplotypes identified in this predominantly Caucasian population. H7 was later redefined by Krauss et al. [8], 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 [8]. 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, or Treatment to New Targets (TNT) studies [8–13]. 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 [6]. As SNP 20144 has been shown to directly influence production of the HMGCR13(−) transcript [5,6], HMGCR alternative splicing is likely one of the molecular mechanisms contributing to the association among 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. Supplemental digital content for the HMGCR gene (PA189) and very important pharmacogene is available at http://www.pharmgkb.org/search/annotatedGene/hmgcr/ http://www.pharmgkb.org/search/annotatedGene/hmgcr/variant.jsp Also known as SNP 12, the estimated allele frequencies of this variant in the predominantly Caucasian PRINCE population (88.7%) are A=0.965 and T=0.035. Complete details of genotypic frequencies are shown in the Table 1. In a study of 1536 individuals, SNP 12 was significantly associated with the mean change in both total and LDL-cholesterol. Heterozygous individuals had a 21.