From SNPedia
| Geno
|
Mag
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Summary
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| (A;A)
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0.1
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normal; no effect on warfarin metabolism
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| (A;C)
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2.1
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CYP2C9*3 carrier; average 40% reduction in warfarin metabolism
|
| (C;C)
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3.5
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CYP2C9*3 homozygote; average 80% reduction in warfarin metabolism
|
| ? | (A;A) (A;C) (C;C) | 28 |
|---|
 |
SNP
rs1057910(A), located in the cytochrome p450
CYP2C9 gene, most commonly encodes the amino acid isoleucine at position 359, and the resulting allele is also known as CYP2C9*1.
rs1057910(C) encodes a leucine at this same position, and the resulting allele is called
CYP2C9*3. This SNP is also known as Ile359Leu or A1075C.
The effect of CYP2C9 variants on drug metabolism should not be predicted without also considering CYP2C9*2, defined as the common loss of function variant rs1799853(T) (NM_000771:c.430C>T, NP_000762:p.144R>C) [PMID 8004131] [1].
Studies of the effects of these alleles include:
- rs1057910(C;C) genotypes may clear drugs like celecoxib (trade name Celebrex) twice as slowly as rs1057910(A;A) genotypes; the rs1057910(A;C) genotypes are in-between clearance rates. Lower clearance rates will lead to higher internal concentrations of the drug. It is not clear whether this could lead to increased efficacy and/or increased side effects. [PMID 12893985]
- rs1057910(C;C) genotypes are poor metabolizers of glipizide, a second generation sulfonylurea drug structurally similar to tolbutamide and also used as an oral hypoglycemic agent. [PMID 10208645]
Individuals carrying this SNP may show increased risk of developing acute gastrointestinal bleeding during the use of NSAIDs that are CYP2C8 or CYP2C9 substrates, such as aceclofenac, celecoxib, diclofenac, ibuprofen, indomethazine, lornoxicam, meloxicam, naproxen, piroxicam, tenoxicam and valdecoxib.[PMID 19422321]
| GWAS snp
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| PMID
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[PMID 19300499]
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| Trait
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Warfarin maintenance dose
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| Title
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A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose
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| Risk Allele
|
|
| P-val
|
3E-79
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| Odds Ratio
|
1.11 [1.00-1.22] mg/week decrease
|
| PharmGKB | PA165111645 |
| Name | CYP2C9*3, c.1075A>C, mRNA 11A>C, p.Ile359Leu |
| Annotation | Risk or phenotype-associated allele: rs1057910 C allele Phenotype: CYP2C9 wild-type (reference) allele carriers required a mean warfarin dose of 3.2 ± 1.6 mg, whereas patients carrying one or two CYP2C9 variant alleles (CYP2C9*2 = rs1799853 T allele, CYP2C9*3 = rs1057910 C allele, relative to CYP2C9*1 = reference) required significantly lower doses (*1/*x: 2.7 ± 1.5 mg (−16%); *x/*x: 1.9 ± 1.1 mg (−41%)) (p = 0.0015). CYP2C9 genotypes showed significant influence on the time to the first INR >=2 (p = 0.0016). The risk for having an INR value >=4 was higher in individuals with multiple variants of CYP2C9 or VKORC1 (rs9923231 A allele) (OR = 12.8, 95% CI = 2.73-60.0). The combined effect of variants and age, explained 26.6% of the variability in the warfarin dose, with VKORC1 (rs9923231 A allele) accounting for 19.1%, CYP2C9 (rs1799853 T allele, or rs1057910 C allele) for 3.2%, EPHX1 (rs2292566 A allele) for 1.7%, CYP4F2 (rs2108622 C allele) for 1.1%, and age for 1.5%. Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): p < = 0.0016. Type of association: GN; PK. |
| Gene | CYP2C9 |
| Featue | Exon/NonSyn |
| Evidence | PubMed ID:19794411 |
| Drugs | warfarin |
| Diseases | |
| Curation Level | Curated |
[PMID 20214591] Pharmacogenomics in aspirin intolerance
[PMID 20555338] Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements
[PMID 20842355] VKORC1-1639G>A, CYP2C9, EPHX1691A>G genotype, body weight, and age are important predictors for warfarin maintenance doses in patients with mechanical heart valve prostheses in southwest China
| PharmGKB | PA161748412 |
| Name | CYP2C9*3:Ile359Leu |
| Annotation | In a GWAS study, this SNP was modestly associated with warfarin dose. |
| Gene | CYP2C9 |
| Featue | Exon/NonSyn |
| Evidence | PubMed ID:18535201 |
| Drugs | warfarin |
| Diseases | |
| Curation Level | Curated |
| PharmGKB | PA162263549 |
| Name | CYP2C9*3, CYP2C9:359Ile>Leu |
| Annotation | In a study on 21 healthy voluntees a more than two-fold reduced oral clearance in homozygous carriers of CYP2C9*3 was seen for celecoxib compared to carriers of the wild-type genotype CYP2C9*1/*1 and the heterozygous carriers of one *3 allele were in-between. CYP2C9*2 had no significant influence on celecoxib pharmacokinetics. |
| Gene | CYP2C9 |
| Featue | Exon/NonSyn |
| Evidence | PubMed ID:12893985 |
| Drugs | celecoxib |
| Diseases | |
| Curation Level | Curated |
| PharmGKB | PA162372807 |
| Name | CYP2C9: I359L, CYP2C9*3 |
| Annotation | This variant (I359L) in exon 7 is part of the CYP2C9*3 allele. The residue 359 is located in the CYP2C9 active site. In vitro studies showed that the rate of losartan oxidation was lower in liver microsomes from individuals carring the CYP2C9*3 allele. This is consitant with an in vivo study showing that the CYP2C9*3 allele is associated with decreased formation of E-3174 (a more potent, active metabolite of losartan) in subjects given a single dose of losartan. |
| Gene | CYP2C9 |
| Featue | Exon/NonSyn |
| Evidence | PubMed ID:11408373; PubMed ID:11823761 |
| Drugs | losartan |
| Diseases | |
| Curation Level | Curated |
| PharmGKB | PA162411186 |
| Name | CYP2C9*3, CYP2C9:359Ile>Leu |
| Annotation | The CYP2C9*3 allele influenced the Factor VII coagulant activity, measured before and 24 hours after acenocoumarol intake, in 263 healthy volunteers. The study conludes that CYP2C9-related genetic variability accounts for 14% of the interindividual variability in acenocoumarol pharmacodynamic response. |
| Gene | CYP2C9 |
| Featue | Exon/NonSyn |
| Evidence | PubMed ID:15116053 |
| Drugs | acenocoumarol |
| Diseases | |
| Curation Level | Curated |
| PharmGKB | PA164739917 |
| Name | |
| Annotation | GWAS results: A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose. (Initial Sample Size: 1,053 individuals; Replication Sample Size: 588 individuals); (Region: 10q23.33; Reported Gene(s): CYP2C9; Risk Allele: rs1057910-?); (p-value= 3E-79).This variant is associated with Warfarin maintenance dose. |
| Gene | CYP2C9 |
| Featue | Exon/NonSyn |
| Evidence | PubMed ID:19300499; Web Resource:http://www.genome.gov/gwastudies/ |
| Drugs | warfarin |
| Diseases | |
| Curation Level | Non-Curated |
| PharmGKB | PA162652684 |
| Name | CYP2C9*3, CYP2C9:359Ile>Leu |
| Annotation | This variant (CYP2C9*3) has been shown to influence warfarin dose and is included in the pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin. |
| Gene | CYP2C9 |
| Featue | Exon/NonSyn |
| Evidence | PubMed ID:19228618 |
| Drugs | warfarin |
| Diseases | |
| Curation Level | Curated |
| PharmGKB | PA165107376 |
| Name | CYP2C9*3, CYP2C9:Ile359Leu |
| Annotation | In a study of Scottish patients receiving sulfonylureas (n=1073), those with any CYP2C9*3 alleles were less likely to experience treatment failure, and CYP2C9*3 homozygotes had greater reductions in HbA(1c) than CYP2C9*1. |
| Gene | CYP2C9 |
| Featue | Exon/NonSyn |
| Evidence | PubMed ID:19794412 |
| Drugs | glibenclamide, gliclazide, glimepiride, glipizide |
| Diseases | Diabetes Mellitus |
| Curation Level | Curated |
| PharmGKB | PA165291906 |
| Name | CYP2C9*3 (A>C) |
| Annotation | Risk or phenotype-associated allele: C allele. Phenotype: Increased warfarin levels given ritonavir/tipranavir. Study size: 23 (7 female). Study population/ethnicity: 16 Caucasians, 7 African American. Significance metric(s): P = 0.047. Type of association: GN; PK. |
| Gene | CYP2C9 |
| Featue | Exon/NonSyn |
| Evidence | PubMed ID:20147896 |
| Drugs | ritonavir, tipranavir, warfarin |
| Diseases | |
| Curation Level | Curated |
| PharmGKB | PA165111639 |
| Name | CYP2C9*3, c.1075A>C, mRNA 11A>C, p.Ile359Leu |
| Annotation | Risk or phenotype-associated allele: CYP2C9*3, rs1057910 C allele, Leu359. Phenotype: Drug response phenotypes included (1) reaching target HbA(1c), (2) maximum HbA(1c) reduction, and (3) time to monotherapy failure. Patients homozygous for the loss-of-function CYP2C9 alleles (*2/*2, *2/*3, *3/*3) achieved greater treatment target (OR = 3.4, p = 0.0009), 0.5% greater reduction in target HbA1c concentration (p = 0.003), and lower risk of monotherapy failure based an additive genetic model (allelic hazard ratio 0.79, 95% confidence interval 0.63-0.99, p = 0.04), compared to wild-type allele (*1) carriers. Study size: 1,073 patients (578 drug-naive, 495 with prior and continued metformin exposure). Study population/ethnicity: Diabetes patients recruited in Tayside, Scotland for the Diabetes Audit and Research Tayside Study (DARTS), between 1992 and 2007, who were incident sulfonylurea users. Significance metric(s): p = (0.04 - 0.0009) Type of association: GN; PD |
| Gene | CYP2C9 |
| Featue | Exon/NonSyn |
| Evidence | PubMed ID:19794412 |
| Drugs | glibenclamide, gliclazide, glimepiride, glipizide, metformin |
| Diseases | Diabetes Mellitus, Type 2 |
| Curation Level | Curated |
[PMID 22321278] [Impact of CYP2C9 and VKORC1 polymorphism on warfarin response during initiation of therapy]
