Important Variant 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 Three Important Variants for HMGCR
1. HMGCR:SNP 12 (rs17244841)
2. HMGCR:SNP 29 (rs17238540)
3. HMGCR:SNP 20144 (rs3846662)
| Gene HGNC Name: | HMGCR |
|---|---|
| Variant Summary: | 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. 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 21.8% 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 (A) allele. There was no genotype effect on HDL-cholesterol changes. These effects remained significant after multiple testing, were not associated with baseline differences, and the LDL-cholesterol effect became stronger after ethnic stratification [PMID: 15199031]. SNP 12 was also reported to be significantly associated with reduced total and LDL-cholesterol response to simvastatin treatment, 6 weeks of 40 mg/day, in the CAP population, comprised of 335 African Americans and 596 Caucasians. Although similar allele frequency and effect sizes were reported between the PRINCE and CAP populations, the relationship was only seen in the African American subset of the CAP cohort [PMID: 18332269]. In contrast, this association was not identified in the ALERT population of 707 Caucasian fluvastatin treated renal transplant patients [PMID: 17563401]. |
| Key PubMed IDs: | 15199031, 18332269, 17563401 |
| Genomic Variant & GenBank ID: | 11898 A>T on AY321356 |
| mRNA Variant & GenBank ID: | Intronic SNP; no mRNA change |
| Protein Variant & GenBank ID: | Intronic SNP; no protein change |
| dbSNP rs#: | rs17244841 |
| GoldenPath Position: | Chr5: 74,678,611 (hg18) |
| Key Drugs/Substrates: | Pravastatin [PMID: 15199031] |
| Key Phenotypes/Diseases: | Attenuated cholesterol reduction with pravastatin treatment [PMID: 15199031] |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): |
White (European): PA126741408 (NA12547), PA126741328 (NA10845), PA126740852 (NA10853), PA126743895 (NA10860), PA126743912 (NA10830), PA126740847 (NA10842), PA126740850 (NA10851), PA126741308 (NA07349), PA126743882 (NA10857), PA126743959 (NA10858), PA126743926 (NA10848), PA126741327 (NA10844), PA126740853 (NA10854), PA126743896 (NA10861), PA126743913 (NA10831), PA126743958 (NA10843), PA126740849 (NA10850), PA126743881 (NA10852), PA126743853 (NA06990), PA126741276 (NA07019) Black or African American (African American): PA126746650 (NA17103), PA126746655 (NA17104), PA126746659 (NA17105), PA126746664 (NA17106), PA126746666 (NA17107), PA126746675 (NA17110), PA126746676 (NA17111), PA126746677 (NA17112), PA126746678 (NA17113), PA126746689 (NA17114), PA126746700 (NA17116), PA126746722 (NA17133), PA126746723 (NA17134), PA126746724 (NA17135), PA126746725 (NA17136), PA126746726 (NA17137), PA126746727 (NA17138), PA126746728 (NA17139), PA126746729 (NA17140) |
| DNA Source Containing Heterozygous Reference Allele(Coriell Lines): |
White (European): PA126741307 (NA07348) Black or African American (African American): PA126746644 (NA17101), PA126746648 (NA17102), PA126746670 (NA17108) |
| Key Haplotypes: | H7 |
| Gene HGNC Name: | HMGCR |
|---|---|
| Variant Summary: | 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 [PMID: 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 [PMID: 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 [PMID: 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 [PMID: 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 [PMID: 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 [PMID: 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 [PMID: 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 [PMID: 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 [PMID: 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 [PMID: 19558216]. In addition, it has also been associated with insulin resistance in women with polycystic ovary syndrome [PMID: 19327767] suggesting that this SNP may be important in non-lipid phenotypes as well. |
| Key PubMed IDs: | 15199031, 16103896, 18332269, 18815589, 17563401, 18261733 |
| Genomic Variant & GenBank ID: | 24558 T>G on AY321356 |
| mRNA Variant & GenBank ID: |
Intronic SNP; no mRNA change |
| Protein Variant & GenBank ID: |
Intronic SNP; no protein change |
| dbSNP rs#: | rs17238540 |
| GoldenPath Position: | chr5:74,691,254 (hg18) |
| Key Drugs/Substrates: | pravastatin [PMID: 15199031, 16103896], atorvastatin, fluvastatin, lovastatin and simvastatin[PMID: 16103896] |
| Key Phenotypes/Diseases: | Attenuated cholesterol reduction with pravastatin treatment [PMID: 15199031] |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): |
White (European): PA126741408 (NA12547), PA126741328 (NA10845), PA126743895 (NA10860), PA126743912 (NA10830), PA126740850 (NA10851), PA126741308 (NA07349), PA126743959 (NA10858), PA126743926 (NA10848), PA126741409 (NA12548), PA126741327 (NA10844), PA126740853 (NA10854), PA126743896 (NA10861), PA126743913 (NA10831), PA126743958 (NA10843), PA126740849 (NA10850), PA126743881 (NA10852), PA126743853 (NA06990), PA126741276 (NA07019) Black or African American (African American): PA126746650 (NA17103), PA126746659 (NA17105), PA126746664 (NA17106), PA126746666 (NA17107), PA126746672 (NA17109), PA126746675 (NA17110), PA126746676 (NA17111), PA126746678 (NA17113), PA126746689 (NA17114), PA126746690 (NA17115), PA126746700 (NA17116), PA126746722 (NA17133), PA126746724 (NA17135), PA126746725 (NA17136), PA126746726 (NA17137), PA126746727 (NA17138), PA126746728 (NA17139) |
| DNA Source Containing Heterozygous Reference Allele (Coriell Lines): |
White (European): PA126741421 (NA12560), PA126741307 (NA07348) Black or African American (African American): PA126746644 (NA17101), PA126746648 (NA17102), PA126746670 (NA17108), PA126746729 (NA17140) |
| Key Haplotypes: | H7 |
3. HMGCR: SNP 20144 (rs3846662)
| Gene HGNC Name: | HMGCR |
|---|---|
| Variant Summary: | Also known as SNP 20144, rs3846662 occurs in the CAP population (Caucasian n=596, African American n=326) at a frequency of A=0.615 and G=0.385, however, the allele frequency varies greatly between racial groups as the "A" allele is significantly more prevalent in the Caucasians compared to the African Americans [PMID: 18332269]. While this SNP by itself is not significantly associated with statin response, it is one of three SNPs which defines HMGCR haplotype 7 (H7), that has been shown to be associated with reduced simvastatin and pravastatin response. In addition, SNP 20144 regulates alternative splicing of HMGCR exon 13 to produce a transcript in which exon 13 has been completely omitted. A GWAS HMGCR SNP, rs12654264, in tight linkage disequilibrium with the SNP 20144 (r2>0.8) has been reported in multiple independent populations to be associated with endogenous variation in plasma LDL-cholesterol [PMID: 18802019, 18354102, 18193044]. |
| Key PubMed IDs: | 18332269, 18559695 |
| Genomic Variant & GenBank ID: | 20144 A>G on AY321356 |
| mRNA Variant & GenBank ID: |
Intronic SNP; no mRNA change |
| Protein Variant & GenBank ID: |
Intronic SNP; no protein change |
| dbSNP rs#: | rs3846662 |
| GoldenPath Position: | chr5:74,686,840 (hg18) |
| Key Drugs/Substrates: | pravastatin [PMID: 15199031, 16103896], atorvastatin, fluvastatin, lovastatin and simvastatin[PMID: 16103896] |
| Key Phenotypes/Diseases: | Attenuated cholesterol reduction with pravastatin treatment [PMID: 15199031] |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): |
White (European): PA126743895 (NA10860), PA126743912 (NA10830), PA126740850 (NA10851), PA126741327 (NA10844), PA126743926 (NA10848), PA126740849 (NA10850), PA126740853 (NA10854), PA126743881 (NA10852), PA126741276 (NA07019) Black or African American (African American): PA126721774 (NA17102), PA126746650 (NA17103), PA126746664 (NA17106), PA126746666 (NA17107), PA126721796 (NA17108), PA126746672 (NA17109), PA126746675 (NA17110), PA126746676 (NA17111), PA126746677 (NA17112), PA126746678 (NA17113), PA126746689 (NA17114), PA126746700 (NA17116), PA126746723 (NA17134), PA126746728 (NA17139), PA126746729 (NA17140) |
| DNA Source Containing Heterozygous Reference Allele (Coriell Lines): |
White (European): PA126743958 (NA10843), PA126743913 (NA10831), PA126741328 (NA10845), PA126743926 (NA10848), PA126743959 (NA10858), PA126743896 (NA10861), PA126741308 (NA07349), PA126743853 (NA06990), PA126741408 (NA12547), PA126741409 (NA12548), PA126740852 (NA10853), PA126740847 (NA10842), PA126743882 (NA10857), PA126741421 (NA12560) Black or African American (African American): PA126746659 (NA17105), PA126746690 (NA17115), PA126746722 (NA17133), PA126746724 (NA17135), PA126746725 (NA17136), PA126746726 (NA17137), PA126746727 (NA17138), PA126746644 (NA17101) |
| Key Haplotypes: | H2,H7 |
| SNP/Haplotype | Population | Individual Group | #Chr | Major Allele | Minor Allele | PMID |
|---|---|---|---|---|---|---|
| SNP 12 (rs17244841) | PRINCE | Caucasian (88.7%) | 2662 | 0.933 | 0.067 | 15199031 |
| major allele = A minor allele = T | ALERT | Caucasian (97.6%) | 1320 | 0.955 | 0.045 | 17563401 |
| European American | 948 | 0.967 | 0.033 | 19327767 | ||
| SNP 29 (rs17238540) | PRINCE | Caucasian (88.7%) | 2662 | 0.933 | 0.067 | 15199031 |
| major allele = T minor allele = G | Go-DARTS | European (Scotland) | 5188 | 0.97 | 0.03 | 18815589 |
| CAP | African American | 652 | 0.926 | 0.074 | 18332269 | |
| European American | 1192 | 0.968 | 0.032 | 18332269 | ||
| ACCESS | Asian | 72 | 1 | 0 | 16103896 | |
| African American | 320 | 0.915 | 0.085 | 16103896 | ||
| Caucasian American | 4908 | 0.972 | 0.028 | 16103896 | ||
| Hispanic | 170 | 0.971 | 0.029 | 16103896 | ||
| ALERT | Caucasian (97.6%) | 1172 | 0.952 | 0.048 | 17563401 | |
| PROSPER | European (Scotland) | 11566 | 0.981 | 0.019 | 18261733 | |
| North Asian Indian | 830 | 0.928 | 0.072 | 19558216 | ||
| European American | 948 | 0.969 | 0.031 | 19327767 | ||
| SNP 20144 (rs3846662) | PARC | African American | 46 | 0.826 | 0.174 | 18332269 |
| major allele = G minor allele = A | European American | 46 | 0.391 | 0.609 | 18332269 | |
| CAP | African American | 652 | 0.873 | 0.127 | 18332269 | |
| European American | 1192 | 0.475 | 0.525 | 18332269 | ||
| European American | 948 | 0.412 | 0.588 | 19327767 | ||
| HapMap | CEU - Caucasian | 120 | 0.458 | 0.542 | ||
| HCB - Asian | 90 | 0.567 | 0.433 | |||
| JPT - Asian | 90 | 0.533 | 0.467 | |||
| YRI - Sub-Saharan African | 120 | 0.933 | 0.067 | |||
| Haplotype 2 | CAP | African American | 652 | 0.68 | 0.32 | 18332269 |
| carrier v. non-carrier | European American | 1192 | 0.98 | 0.02 | 18332269 | |
| European American | 948 | 0.956 | 0.044 | 19327767 | ||
| Haplotype7 | CAP | African American | 652 | 0.94 | 0.06 | 18332269 |
| carrier v. non-carrier | European American | 1192 | 0.97 | 0.03 | 18332269 | |
| European American | 948 | 0.969 | 0.031 | 19327767 |
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