CYP2C9 I359L - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

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Curation:
Currentness:

CYP2C9 I359L

(CYP2C9 Ile359Leu)


Short summary

This variant, also called CYP2C9*3, is a pharmacogenetic variant that modulates sensitivity for Warfarin (due to reduced metabolism). This variant is more frequent in Caucasians. The FDA has approved reduced recommended Warfarin dosage based on the presence of this variant.

Variant evidence
Computational 1

Other variants in this gene have pharmacogenetic effect

See unpublished research (below).

Functional 3

Variant has ~90% reduced metabolism, decreased coupling, substantially lower percent high spin enzyme compared to wild-type

See Sconce EA et al. 2005 (15947090), Wei L et al. 2007 (17686967), unpublished research (below).

Case/Control 5

Well-established pharmacogenetic variant.

See unpublished research (below).

Familial -
 
Clinical importance
Severity 4

Warfarin overdose can cause life-threatening internal bleeding.

See unpublished research (below).

Treatability 4

FDA has approved of adjustment of warfarin dosage based on CYP2C9 variants.

See Sconce EA et al. 2005 (15947090), unpublished research (below).

Penetrance -
 

Impact

Insufficiently evaluated pharmacogenetic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • C @ chr10:96741053: 4.9% (527/10758) in EVS
  • C @ chr10:96731042: 1.6% (2/128) in GET-Evidence
  • Frequency shown in summary reports: 4.9% (527/10758)

Publications
 

Kirchheiner J, Störmer E, Meisel C, Steinbach N, Roots I, Brockmöller J. Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Pharmacogenetics. 2003 Aug;13(8):473-80. PubMed PMID: 12893985.

 

Morin S, Bodin L, Loriot MA, Thijssen HH, Robert A, Strabach S, Verstuyft C, Tregouet DA, Dubert L, Laurent-Puig P, Funck-Brentano C, Jaillon P, Beaune PH, Becquemont L. Pharmacogenetics of acenocoumarol pharmacodynamics. Clin Pharmacol Ther. 2004 May;75(5):403-14. PubMed PMID: 15116053.

 

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.

 

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
 

Other external references
 

    dbSNP
  • rs1057910
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [fluvastatin; glipizide; phenytoin; tolbutamide; warfarin]
    This variant has been shown to correlate significantly with warfarin dose as well as affecting the clearance of several other drugs.
    www.pharmgkb.org/search/annotatedGene/cyp2c9
  • [celecoxib]
    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.
    www.ncbi.nlm.nih.gov/pubmed/12893985
  • [acenocoumarol]
    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.
    www.ncbi.nlm.nih.gov/pubmed/15116053
  • [warfarin]
    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.
    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*3 alleles were less likely to experience treatment failure, and CYP2C9*3 homozygotes had greater reductions in HbA(1c) than CYP2C9*1.
    www.ncbi.nlm.nih.gov/pubmed/19794412
    PolyPhen-2
  • Score: 0.048 (benign)

Other in silico analyses
 

  • NBLOSUM100 score = –2
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

"GENE" or "GENE A123C":

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