Gene:
HMGCR
3-hydroxy-3-methylglutaryl-CoA reductase

PharmGKB contains no dosing guidelines for this . To report known genotype-based dosing guidelines, or if you are interested in developing guidelines, click here.

PharmGKB has no annotated drug labels with pharmacogenomic information for this . If you know of a drug label with PGx, send us a message.

PharmGKB contains no Clinical Variants that meet the highest level of criteria.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the table.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page on the appropriate tab.

Links in the "Drugs" column lead to PharmGKB Drug Pages.

List of all variant annotations for HMGCR

Variant?
(147)
Alternate Names ? Chemicals ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available CA VA H2 N/A N/A N/A
No VIP available CA VA H7 N/A N/A N/A
No VIP available No Clinical Annotations available VA
rs10474433 NC_000005.10:g.75321018T>C, NC_000005.9:g.74616843T>C, rs17739061, rs52795663, rs59014840
T > C
SNP
No VIP available CA VA
rs12654264 NC_000005.10:g.75352778A>T, NC_000005.9:g.74648603A>T, NG_011449.1:g.20611A>T, NM_000859.2:c.1368+1176A>T, NM_001130996.1:c.1368+1176A>T, XM_005248492.1:c.1428+1176A>T, XM_011543357.1:c.1428+1176A>T, XM_011543358.1:c.1368+1176A>T, XM_011543359.1:c.1428+1176A>T, rs17562575, rs56464192, rs58426549
A > T
SNP
rs17238540 NC_000005.10:g.75359673T>G, NC_000005.9:g.74655498T>G, NG_011449.1:g.27506T>G, NM_000859.2:c.2457+117T>G, NM_001130996.1:c.2298+117T>G, XM_005248492.1:c.2517+117T>G, XM_011543357.1:c.2517+117T>G, XM_011543358.1:c.2457+117T>G, XM_011543359.1:c.2358+117T>G, rs59500163
T > G
SNP
rs17244841 NC_000005.10:g.75347030A>T, NC_000005.9:g.74642855A>T, NG_011449.1:g.14863A>T, NM_000859.2:c.451-174A>T, NM_001130996.1:c.451-174A>T, XM_005248492.1:c.511-174A>T, XM_011543357.1:c.511-174A>T, XM_011543358.1:c.451-174A>T, XM_011543359.1:c.511-174A>T, rs60168925
A > T
SNP
No VIP available CA VA
rs17671591 NC_000005.10:g.75319196C>T, NC_000005.9:g.74615021C>T, rs57833312
C > T
SNP
rs3846662 NC_000005.10:g.75355259A>G, NC_000005.9:g.74651084A>G, NG_011449.1:g.23092A>G, NM_000859.2:c.1722+45A>G, NM_001130996.1:c.1564-106A>G, XM_005248492.1:c.1782+45A>G, XM_011543357.1:c.1782+45A>G, XM_011543358.1:c.1722+45A>G, XM_011543359.1:c.1624-106A>G, rs17238505, rs17562582, rs386587624, rs56538861, rs59397732
A > G
SNP
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 147

Overview

Alternate Names:  3-hydroxy-3-methylglutaryl CoA reductase (NADPH); hydroxymethylglutaryl-CoA reductase
Alternate Symbols:  None
PharmGKB Accession Id: PA189

Details

Cytogenetic Location: chr5 : q13.3 - q13.3
GP mRNA Boundary: chr5 : 74632159 - 74657926
GP Gene Boundary: chr5 : 74622159 - 74660926
Strand: plus

Visualization

UCSC has a Genome Browser that you can use to view PharmGKB annotations for this gene in context with many other sources of information.

View on UCSC Browser
The mRNA boundaries are calculated using the gene's default feature set from NCBI, mapped onto the UCSC Golden Path. PharmGKB sets gene boundaries by expanding the mRNA boundaries by no less than 10,000 bases upstream (5') and 3,000 bases downstream (3') to allow for potential regulatory regions.

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 [Article:1967820]. The inhibition of these small GTP-binding proteins is thought to mediate the pleiotropic effects of statins [Article: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 [Article:1967820]. The HMGCR gene is found on chromosome 5q13.3-q14 [Article: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 [Article: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 [Article: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. [Article: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 [Article: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 [Article: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 [Article:18559695]. Since SNP 20144 has been shown to directly influence production of the HMGCR13( - ) transcript [Article: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.

Citation PharmGKB: very important pharmacogene--HMGCR. Pharmacogenetics and genomics. 2011. Medina Marisa Wong, Sangkuhl Katrin, Klein Teri E, Altman Russ B. PubMed
History

Submitted by Marisa Wong Medina (PARC), Katrin Sangkuhl

Variant Summaries rs17238540, rs17244841, rs3846662
Haplotype Summaries HMGCR:H7, HMGCR:H2
Drugs
Phenotypes Attenuated cholesterol reduction with pravastatin treatment

Haplotype Overview

Haplotypes as described in [Article:18332269].

Source: PharmGKB

All alleles in the download file are on the positive chromosomal strand. PharmGKB considers the first haplotype listed in each table as the reference haplotype for that set.

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

  1. Bisphosphonate Pathway, Pharmacodynamics
    Representation of genes involved in bisphosphonates' effects in osteoclasts.
  1. Statin Pathway, Pharmacodynamics
    Genes involved in mediating statin effects on hepatic cholesterol metabolism and consequent effects on plasma lipoprotein transport.

External Pathways

Links to non-PharmGKB pathways.

PharmGKB contains no links to external pathways for this gene. To report a pathway, click here.

Curated Information ?

Curated Information ?

Curated Information ?

Publications related to HMGCR: 31

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Seventeen years of statin pharmacogenetics: a systematic review. Pharmacogenomics. 2016. Leusink Maarten, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia. Pharmacogenetics and genomics. 2015. Leduc Valerie, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
HMGCR rs17671591 SNP determines Lower Plasma LDL-C after Atorvastatin Therapy in Chilean Individuals. Basic & clinical pharmacology & toxicology. 2015. Cuevas Alejandro, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A statin-dependent QTL for GATM expression is associated with statin-induced myopathy. Nature. 2013. Mangravite Lara M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenomics: the genetics of variable drug responses. Circulation. 2011. Roden Dan M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenomics of the RNA world: structural RNA polymorphisms in drug therapy. Clinical pharmacology and therapeutics. 2011. Sadee W, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Effect of HMGCR Variant Alleles on Low-Density Lipoprotein Cholesterol-Lowering Response to Atorvastatin in Healthy Korean Subjects. Journal of clinical pharmacology. 2011. Chung Jae Yong, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
PharmGKB summary: methotrexate pathway. Pharmacogenetics and genomics. 2011. Mikkelsen Torben S, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
PharmGKB: very important pharmacogene--HMGCR. Pharmacogenetics and genomics. 2011. Medina Marisa Wong, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Single nucleotide polymorphisms in genes that are associated with a modified response to statin therapy: the Rotterdam Study. The pharmacogenomics journal. 2011. de Keyser C E, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Replication of LDL GWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses. BMC medical genetics. 2011. Trompet Stella, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin. Arteriosclerosis, thrombosis, and vascular biology. 2010. Mangravite Lara M, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer. Cancer prevention research (Philadelphia, Pa.). 2010. Lipkin Steven M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A gene score of nine LDL and HDL regulating genes is associated with fluvastatin-induced cholesterol changes in women. Journal of lipid research. 2010. Hamrefors Viktor, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Common sequence variants in pharmacodynamic and pharmacokinetic pathway-related genes conferring LDL cholesterol response to statins. Pharmacogenomics. 2010. Chien Kuo-Liong, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
HMGCR gene polymorphism is associated with stroke risk in the EPIC-Norfolk study. European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology. 2010. Freitas Renata N, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
The role of HMGCR alternative splicing in statin efficacy. Trends in cardiovascular medicine. 2009. Medina Marisa Wong, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Comprehensive whole-genome and candidate gene analysis for response to statin therapy in the Treating to New Targets (TNT) cohort. Circulation. Cardiovascular genetics. 2009. Thompson John F, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A HMGCR polymorphism is associated with relations between blood pressure and urinary sodium and potassium ratio in the Epic-Norfolk Study. Journal of the American Society of Hypertension : JASH. 2009. Freitas Renata N, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
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. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacological effects of lipid-lowering drugs recapitulate with a larger amplitude the phenotypic effects of common variants within their target genes. Pharmacogenetics and genomics. 2008. Knouff Christopher W, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
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. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Common genetic variation in six lipid-related and statin-related genes, statin use and risk of incident nonfatal myocardial infarction and stroke. Pharmacogenetics and genomics. 2008. Hindorff Lucia A, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Alternative splicing of 3-hydroxy-3-methylglutaryl coenzyme A reductase is associated with plasma low-density lipoprotein cholesterol response to simvastatin. Circulation. 2008. Medina Marisa Wong, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
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. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genetic analysis of fluvastatin response and dyslipidemia in renal transplant recipients. Journal of lipid research. 2007. Singer Jonathan B, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
An association study of 43 SNPs in 16 candidate genes with atorvastatin response. The pharmacogenomics journal. 2005. Thompson J F, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action?. The pharmacogenomics journal. 2005. Fernø J, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Statin myotoxicity is associated with changes in the cardiopulmonary function. Atherosclerosis. 2004. Phillips P S, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA : the journal of the American Medical Association. 2004. Chasman Daniel I, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. Blood. 2003. Ross Mary E, et al. PubMed

LinkOuts

NCBI Gene:
3156
OMIM:
142910
UCSC Genome Browser:
NM_000859
RefSeq RNA:
NM_000859
NM_001130996
RefSeq Protein:
NP_000850
NP_001124468
RefSeq DNA:
NG_011449
NT_006713
UniProtKB:
HMDH_HUMAN (P04035)
Ensembl:
ENSG00000113161
GenAtlas:
HMGCR
GeneCard:
HMGCR
MutDB:
HMGCR
ALFRED:
LO069456E
HuGE:
HMGCR
Comparative Toxicogenomics Database:
3156
ModBase:
P04035
HumanCyc Gene:
HS03652
HGNC:
5006

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