CYP2C9 R144C - GET-Evidence

Curation:
Currentness:

CYP2C9 R144C

(CYP2C9 Arg144Cys)


Short summary

This variant, also called CYP2C9*2, is a pharmacogenetic variant that modulates sensitivity for Warfarin (due to reduced metabolism). This variant is associated with Caucasians. The FDA has approved reduced recommended Warfarin dosage based on the presence of this variant.

Variant evidence
Computational 2

Other variants in this gene have pharmacogenetic effect, NBLOSUM100=5

See unpublished research (below).

Functional 3

Variant protein has 30-50% reduced rate of metabolism at high substrate concentrations, decreased coupling efficiency, excess water formation

See Rettie AE et al. 1994 (8004131), Wei L et al. 2007 (17686967), unpublished research (below).

Case/Control 4

Well-established pharmacogenetic variant.

See unpublished research (below).

Familial -
 
Clinical importance
Severity 3

Warfarin overdose can cause life-threatening internal bleeding, but dosing guidelines would involve adjustments which should address this

Treatability 3

FDA has approved of adjustment of warfarin dosage based on CYP2C9 variants, although it is not required (biochemical testing can be used to adjust dosage)

See Sconce EA et al. 2005 (15947090).

Penetrance 3

Moderate impact on dose

 

Impact

Moderate clinical importance, pharmacogenetic

(The "moderate clinical importance, " qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr10:96702047: 9.7% (1044/10752) in EVS
  • T @ chr10:96692036: 8.6% (11/128) in GET-Evidence
  • Frequency shown in summary reports: 9.7% (1044/10752)

Publications
 

Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics. 1994 Feb;4(1):39-42. PubMed PMID: 8004131.

 

Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood P, Kesteven P, Daly AK, Kamali F. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005 Oct 1;106(7):2329-33. Epub 2005 Jun 9. PubMed PMID: 15947090.

Proposes the formula for warfarin dosing: dose = 0.628 − 0.0135 (age in years) − 0.240 (# of CYP2C9*2 copies) − 0.370 (# of CYP2C9*3 copies) − 0.241 (# of VKORC1 -1639 G to A) + 0.0162 (height in cm)

Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 - rationale and perspectives. Thromb Res. 2007;120(1):1-10. Epub 2006 Dec 11. Review. PubMed PMID: 17161452.

 

Wei L, Locuson CW, Tracy TS. Polymorphic variants of CYP2C9: mechanisms involved in reduced catalytic activity. Mol Pharmacol. 2007 Nov;72(5):1280-8. Epub 2007 Aug 8. PubMed PMID: 17686967; PubMed Central PMCID: PMC2377026.

 

International Warfarin Pharmacogenetics Consortium, Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009 Feb 19;360(8):753-64. Erratum in: N Engl J Med. 2009 Oct 15;361(16):1613. Dosage error in article text. PubMed PMID: 19228618; PubMed Central PMCID: PMC2722908.

 

Pautas E, Moreau C, Gouin-Thibault I, Golmard JL, Mahé I, Legendre C, Taillandier-Hériche E, Durand-Gasselin B, Houllier AM, Verrier P, Beaune P, Loriot MA, Siguret V. Genetic factors (VKORC1, CYP2C9, EPHX1, and CYP4F2) are predictor variables for warfarin response in very elderly, frail inpatients. Clin Pharmacol Ther. 2010 Jan;87(1):57-64. Epub 2009 Sep 30. PubMed PMID: 19794411.

 

Zhou K, Donnelly L, Burch L, Tavendale R, Doney AS, Leese G, Hattersley AT, McCarthy MI, Morris AD, Lang CC, Palmer CN, Pearson ER. Loss-of-function CYP2C9 variants improve therapeutic response to sulfonylureas in type 2 diabetes: a Go-DARTS study. Clin Pharmacol Ther. 2010 Jan;87(1):52-6. Epub 2009 Sep 30. PubMed PMID: 19794412.

 

Genomes
 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het T @ chr10:96702047

 

hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
het T @ chr10:96702047

 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
hom T @ chr10:96702047

 

hu4339C0 - CGI sample GS01175-DNA_H01 from PGP sample 94797469
het T @ chr10:96702047

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het T @ chr10:96702047

 

hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
het T @ chr10:96702047

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
hom T @ chr10:96702047

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het T @ chr10:96702047

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
hom T @ chr10:96702047

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
het T @ chr10:96702047

 

GS06994 - var-GS06994-1100-36-ASM
het T @ chr10:96692037

 

Other external references
 

    dbSNP
  • rs1799853
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GWAS
  • Warfarin maintenance dose (rs1799853-?)
    Takeuchi 20-Mar-09 in PLoS Genet
    OR or beta: 0.54 [0.45-0.63] mg/week decrease
    Risk allele frequency: 0.11
    p-value: 1.00E-31
    Initial sample: 1,053 individuals
    Replication sample: 588 individuals
    www.ncbi.nlm.nih.gov/pubmed/19300499
    PharmGKB
  • [warfarin]
    Risk or phenotype-associated allele: rs1799853 T allele Phenotype: CYP2C9 wild-type (reference) allele carriers required a mean warfarin dose of 3.2 &#177; 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 &#177; 1.5 mg (&#8722;16%); *x/*x: 1.9 &#177; 1.1 mg (&#8722;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.
    www.ncbi.nlm.nih.gov/pubmed/19794411
  • [fluvastatin; glipizide; phenytoin; tolbutamide; warfarin]
    This variant has been shown to influence warfarin dose as well as affecting the clearance of several other drugs.
    www.pharmgkb.org/search/annotatedGene/cyp2c9
  • [warfarin]
    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: rs1799853-?); (p-value= 1E-31).This variant is associated with Warfarin maintenance dose.
    www.ncbi.nlm.nih.gov/pubmed/19300499; Web Resource:http://www.genome.gov/gwastudie
  • [warfarin]
    This variant (CYP2C9*2) has been shown to influence warfarin dose and is included in the pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin.
    www.ncbi.nlm.nih.gov/pubmed/19228618
  • [Diabetes Mellitus]
    [glibenclamide; gliclazide; glimepiride; glipizide]
    In a study of Scottish patients receiving sulfonylureas (n=1073), those with any CYP2C9*2 alleles were less likely to experience treatment failure, and CYP2C9*2 homozygotes had greater reductions in HbA(1c) than CYP2C9*1.
    www.ncbi.nlm.nih.gov/pubmed/19794412
  • [Diabetes Mellitus, Type 2]
    [glibenclamide; gliclazide; glimepiride; glipizide; metformin]
    Risk or phenotype-associated allele: CYP2C9*2, rs1799853 T allele, Cys144. 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
    www.ncbi.nlm.nih.gov/pubmed/19794412
    PolyPhen-2
  • Score: 0.954 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 8
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in