Variant:

rs17238540 at chr5:74655498 in HMGCR (VIP)

Clinical Annotations

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Variant Annotations

PharmGKB variant annotations provide information about variant-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.

Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.

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There are 1 disease-related annotations for this variant. Register or sign in to see them.

VIP Variant in HMGCR

Rs17238540, also known as SNP 29, is found in tight linkage disequilibrium (r2>0.9) with SNP 12, with identical allele frequencies reported in the PRINCE population, T=0.965 and G=0.035 [Article:15199031]. The GoDARTS Caucasian population reported a similar minor allele frequency of 0.033 (N=1601), while the ACCESS trial reported a minor allele frequency of 0.0 in Asians (N=36), 0.085 in African Americans (N=160), 0.027 in Caucasians (2454) and 0.029 in Hispanics (N=85).

Association between SNP 29 and attenuated statin response has been reported in three independent populations. In the PRINCE trial, similar to SNP 12, SNP 29 was also significantly associated with the mean change in both total and LDL-cholesterol response to pravastatin [Article:15199031]. Heterozygous individuals had a 22.3% reduction in total cholesterol lowering and a 19.0% reduction in LDL-cholesterol lowering after pravastatin treatment as compared to individuals homozygous for the major allele. In the CAP trial, African American SNP 29 carriers had reduced total cholesterol and LDL-cholesterol lowering, 14.1% and 12.2% respectively, in response to simvastatin treatment compared to SNP 29 non-carriers [Article:18332269]. Similarly, the GoDARTs study of 1601 Caucasians treated with a variety of different statins (predominantly simvastatin), also reported SNP 29 heterozygotes had a 13% smaller reduction in total cholesterol and a 27% smaller reduction in triglycerides compared to non-carriers [Article:18815589].

The association between SNP 29 and LDL-cholesterol reduction with statin treatment was not replicated in either the ACCESS, ALERT, PROSPER or TNT studies [Article:16103896, 17563401, 18261733]. The ACCESS trial reported no significant association between SNP 29 and LDL-cholesterol reduction in 293 genotyped Caucasian individuals treated with pravastatin for 24 weeks. The trial also included 1902 individuals treated with atorvastatin, 477 individuals with fluvastatin, 476 individuals with lovastatin, and 468 individuals with simvastatin, however no other associations between SNP29 and statin efficacy were reported [Article:16103896]. The ALERT study included 707 Caucasian fluvastatin treated (40-80mg/day) renal transplant recipients, and while no significant SNP 29 effect was found, the data suggested trends in the same direction as those reported in the PRINCE trial [Article:17563401]. Lastly, in 2891 elderly (aged 70-82) pravastatin treated (40mg/day) Caucasians comprising the PROSPER trial, no association was found between SNP 29 and either LDL-cholesterol response to pravastatin or coronary heart disease or cardiovascular disease event rates. However, the SNP29 allele frequency was notably more rare in the PROSPER population (1.9% carrier) compared to the PRINCE population [Article:18261733]. Lastly, the TNT study included 5745 individuals with European ancestry treated with atorvastatin, 10-80 mg/day. Although no association between SNP 29 and LDL-cholesterol response to atorvastatin was identified, the authors were unable to rule out if a lack of replication was due to a statin specific effect.

Despite this lack of replication, SNP 29 has also been reported to be associated with baseline lipid levels [Article:18332269]. Most recently, this SNP was found to be associated with greater total and LDL-cholesterol in a population of 265 North Indian patients with coronary artery disease [Article:19558216]. In addition, it has also been associated with insulin resistance in women with polycystic ovary syndrome [Article:19327767] suggesting that this SNP may be important in non-lipid phenotypes as well.

Frequency Table

Publications related to rs17238540 at chr5:74655498: 6

CA VA VIP	Genetic variation at the LDL receptor and HMG-CoA reductase gene loci, lipid levels, statin response, and cardiovascular disease incidence in PROSPER. Atherosclerosis. 2008. Polisecki Eliana, et al. [Article:18261733@PubMed]
CA VA VIP	Variation in the 3-hydroxyl-3-methylglutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment. Circulation. 2008. Krauss Ronald M, et al. [Article:18332269@PubMed]
CA VA VIP	A paucimorphic variant in the HMG-CoA reductase gene is associated with lipid-lowering response to statin treatment in diabetes: a GoDARTS study. Pharmacogenetics and genomics. 2008. Donnelly Louise A, et al. [Article:18815589@PubMed]
CA VA VIP	Genetic analysis of fluvastatin response and dyslipidemia in renal transplant recipients. Journal of lipid research. 2007. Singer Jonathan B, et al. [Article:17563401@PubMed]
CA VA VIP	An association study of 43 SNPs in 16 candidate genes with atorvastatin response. The pharmacogenomics journal. 2005. Thompson J F, et al. [Article:16103896@PubMed]
CA VA VIP	Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA : the journal of the American Medical Association. 2004. Chasman Daniel I, et al. [Article:15199031@PubMed]

Cross-References

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