Important Haplotype 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
There are Two Important Haplotype for HMGCR.
| Gene HGNC Name: | HMGCR |
|---|---|
| Haplotype Significance: | Identified by Chasman et al. [PMID: 15199031], HMGCR H7 was originally defined by SNPs 12 and 29, and found to be associated with reduced total cholesterol and LDL-cholesterol response to pravastatin therapy [PMID: 15199031]. However, with additional resequencing and genotyping of tagSNPs spanning the entire HMGCR gene, Krauss et al. found that the H7 haplotype also includes SNP 20144 [PMID: 18332269]. While the original two SNP definition of H7 did not offer additional information than either SNP 12 or SNP 29 alone, the three SNP definition has added value over the SNPs alone as SNP 20144 is found in two different haplotypes, H7 and H2. In the CAP population, African American H7 carriers had a 20.5% smaller reduction of total cholesterol and 24.4% smaller reduction of LDL-cholesterol in response to simvastatin treatment compared to non-carriers, p=0.002 and p=0.0009 respectively. The H7 haplotype is found in 3% of Caucasians and 6% of African Americans [PMID: 18332269]. Alternative splicing of exon 13 of the HMGCR transcript is likely one of the molecular mechanisms underlying the association between H7 and statin response. Through in vitro statin incubation experiments of immortalized lymphocyte cell lines derived from the CAP individuals, Medina et al. reported that SNP 20144 is associated with statin-induced expression of the HMGCR transcript without exon 13, HMGCR13( - ), a finding that was independently validated using expression constructs [PMID: 18559695, 18802019]. In addition, greater in vitro statin-induced HMGCR13( - ) expression was found to be significantly related to smaller in vivo reductions of plasma total cholesterol, LDL cholesterol, apoB and triglycerides. Furthermore, artificial enrichment of the HMGCR13( - ) transcript via siRNA resulted in cells with reduced statin sensitivity, suggesting that the association between H7 with attenuated statin response is due to variation in the production of an HMGCR isoform with reduced statin sensitivity [PMID: 18559695]. HMGCR H7 has also been found to be associated with baseline lipid levels in both the CAP and The Multi-Ethnic Study of Atherosclerosis (MESA) populations. CAP African American H7 carriers had lower baseline total cholesterol, LDL-cholesterol and apoB compared to non-carriers [PMID: 18332269]. In the MESA population consisting of 597 African Americans, 627 Chinese Americans, 612 European Americans and 108 Hispanic Americans, a haplotype containing SNPs 12, 20144 and 29 was reported to be associated with significantly lower levels of triglycerides in the African American and Hispanic American ethnic groups within MESA population [PMID: 19554360]. |
| Does this haplotype span more than one gene? | No |
| Definitive Publication or Website: | 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]. Variation in the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene is association with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment. Krauss RM, Mangravite LM, Smith JD, Medina MW, Wang D, Gua X, Rieder MJ, Simon JA, Hulley SB, Waters D, Saad M, Williams PT, Taylor KD, Yang H, Nickerson DA, Rotter JI. Circulation. 2008. 117:1537-1544 [PMID: 18332269]. |
| Key PubMed IDs: | 15199031, 18332269, 18559695, 18802019 |
| How many SNPs, indels, repeats define this haplotype? | Three SNPs (SNP12, SNP29, and SNP20144) define H7; however 33 SNPs were genotyped during identification. |
| Gene HGNC Name: | HMGCR |
|---|---|
| Haplotype Significance: | Originally identified by Krauss et al. [PMID: 18332269], HMGCR haplotype 2 is defined as the combination of common alleles across 11 tagSNPs within HMGCR, and is found at a frequency of 0.32 in African Americans and 0.02 in Caucasians. H2 carriers had 10.3% smaller reductions of total cholesterol and 10.0% smaller reductions of LDL-cholesterol in the African American subset of the CAP population, p<0.05. Although this relationship was not as prominent as the H7 haplotype, notably, individuals who carry both the H2 and H7 HMGCR haplotypes have even further reductions in the LDL-cholesterol response compared to either H2 or H7 carriers alone [PMID: 18332269]. Since H2/H7 carriers are effectively SNP 20144 homozygotes who also carry SNPs 12 and 29, and SNP 20144 is a known genetic determinant of HMGCR exon 13 alternative splicing, it is likely that the relationship between both H2 and H7 with statin response is driven by regulation of exon 13 alternative splicing [PMID: 18559695]. |
| Does this haplotype span more than one gene? | No |
| Definitive Publication or Website: | Variation in the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment. Krauss RM, Mangravite LM, Smith JD, Medina MW, Wang D, Gua X, Rieder MJ, Simon JA, Hulley SB, Waters D, Saad M, Williams PT, Taylor KD, Yang H, Nickerson DA, Rotter JI. Circulation. 2008. 117:1537-1544 [PMID: 18332269]. Alternative splicing of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene is associated with plasma low density lipoprotein cholesterol response to simvastatin. Medina MW, Gao F, Ruan W, Rotter JI, Krauss RM. Circulation. 2008. 118:355-362 [PMID: 18559695]. |
| Key PubMed IDs: | 18559695, 18332269 |
| How many SNPs, indels, repeats define this haplotype? | 11 tagSNPs |
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