CYP4F2 V433M - GET-Evidence

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

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Curation:
Currentness:

CYP4F2 V433M

(CYP4F2 Val433Met)


Short summary

Requires 1mg/day greater dose of warfarin.

Variant evidence
Computational -
Functional -
Case/Control -
Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Insufficiently evaluated pharmacogenetic

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

Inheritance pattern

recessive

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr19:15990431: 22.6% (2426/10758) in EVS
  • T @ chr19:15851430: 21.9% (28/128) in GET-Evidence
  • Frequency shown in summary reports: 22.6% (2426/10758)

Publications
 

Pérez-Andreu V, Roldán V, Antón AI, García-Barberá N, Corral J, Vicente V, González-Conejero R. Pharmacogenetic relevance of CYP4F2 V433M polymorphism on acenocoumarol therapy. Blood. 2009 May 14;113(20):4977-9. Epub 2009 Mar 6. PubMed PMID: 19270263.

 

McDonald MG, Rieder MJ, Nakano M, Hsia CK, Rettie AE. CYP4F2 is a vitamin K1 oxidase: An explanation for altered warfarin dose in carriers of the V433M variant. Mol Pharmacol. 2009 Jun;75(6):1337-46. Epub 2009 Mar 18. PubMed PMID: 19297519; PubMed Central PMCID: PMC2684883.

 

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.

 

Perini JA, Struchiner CJ, Silva-Assunção E, Suarez-Kurtz G. Impact of CYP4F2 rs2108622 on the stable warfarin dose in an admixed patient cohort. Clin Pharmacol Ther. 2010 Apr;87(4):417-20. Epub 2010 Feb 24. PubMed PMID: 20182420.

 

Genomes
 

hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het T @ chr19:15990431

 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het T @ chr19:15990431

 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het T @ chr19:15990431

 

hu0E64A1 - CGI sample GS01173-DNA_B02 from PGP sample 94378523
hom T @ chr19:15990431

 

hu342A08 - CGI sample GS01175-DNA_B05 from PGP sample 83494370
het T @ chr19:15990431

 

 

hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het T @ chr19:15990431

 

hu4339C0 - CGI sample GS01175-DNA_H01 from PGP sample 94797469
het T @ chr19:15990431

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het T @ chr19:15990431

 

hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
hom T @ chr19:15990431

 

hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
het T @ chr19:15990431

 

hu7A4AD1 - CGI sample GS01669-DNA_C05 from PGP sample 42408046
hom T @ chr19:15990431

 

hu92C40A - CGI sample GS01175-DNA_G03 from PGP sample 92527586
het T @ chr19:15990431

 

hu92FD55 - CGI sample GS01669-DNA_A04 from PGP sample 08188426
het T @ chr19:15990431

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het T @ chr19:15990431

 

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het T @ chr19:15990431

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het T @ chr19:15990431

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
het T @ chr19:15990431

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
hom T @ chr19:15990431

 

huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
het T @ chr19:15990431

 

huFFAD87 - CGI sample GS01669-DNA_H05 from PGP sample 10971581
het T @ chr19:15990431

 

GS06994 - var-GS06994-1100-36-ASM
hom T @ chr19:15851431

 

GS18517 - var-GS18517-1100-36-ASM
het T @ chr19:15851431

 

GS18526 - var-GS18526-1100-36-ASM
het T @ chr19:15851431

 

GS18558 - var-GS18558-1100-36-ASM
hom T @ chr19:15851431

 

GS19648 - var-GS19648-1100-36-ASM
hom T @ chr19:15851431

 

GS19669 - var-GS19669-1100-36-ASM
het T @ chr19:15851431

 

GS19670 - var-GS19670-1100-36-ASM
het T @ chr19:15851431

 

GS20502 - var-GS20502-1100-36-ASM
het T @ chr19:15851431

 

GS21767 - var-GS21767-1100-36-ASM
hom T @ chr19:15851431

 

NA12878

 

Other external references
 

    dbSNP
  • rs2108622
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GWAS
  • Acenocoumarol maintenance dosage (rs2108622-?)
    Teichert 4-Jul-09 in Hum Mol Genet
    OR or beta: NR NR
    p-value: 3.00E-10
    Initial sample: 1,451 Caucasian individuals
    Replication sample: 287 Caucasian individuals
    www.ncbi.nlm.nih.gov/pubmed/19578179
  • Warfarin maintenance dose (rs2108622-?)
    Takeuchi 20-Mar-09 in PLoS Genet
    OR or beta: 0.21 [0.14-0.27] mg/week increase
    Risk allele frequency: 0.24
    p-value: 3.00E-10
    Initial sample: 1,053 individuals
    Replication sample: 588 individuals
    www.ncbi.nlm.nih.gov/pubmed/19300499
    PharmGKB
  • [warfarin]
    Risk or phenotype-associated allele: no allelic association. Phenotype: Improved pharmacogenetic algorithm-based warfarin dosing. Study size: 370. Study population/ethnicity: Self identified white, black, or "intermediate" Brazilians. Significance metric(s): p > 0.05. Type of association: PK.
    www.ncbi.nlm.nih.gov/pubmed/20182420
  • [warfarin]
    Risk or phenotype-associated allele: A allele Phenotype: The A allele was not associated with variability in warfarin maintenance dose (p = 0.1270), however the combined effect of variants and age explained 26.6% of the overall interindividual in warfarin dose variability, 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) gentoypes 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): mixed. Type of association: GN; PK.
    www.ncbi.nlm.nih.gov/pubmed/19794411
  • [warfarin]
    This variant is found to have clinical impact on stable warfarin dose. Patients with 2 TT alleles were reported to require approximately 1 mg/day more warfarin than patients with 2 CC alleles. This variant affects enzyme acitivity and was shown to decrease 20-HETE production in a reconstituted recombinant protein system to approximately 60% of the wild-type enzyme.
    www.ncbi.nlm.nih.gov/pubmed/17341693; PubMed ID:18250228
  • [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: 19p13.12; Reported Gene(s): CYP4F2; Risk Allele: rs2108622-?); (p-value= 0.0000000003).This variant is associated with Warfarin maintenance dose.
    www.ncbi.nlm.nih.gov/pubmed/19300499; Web Resource:http://www.genome.gov/gwastudie
  • [warfarin]
    An in-vitro study demonstrated that CYP4F2 is a vitamin K(1) oxidase and that carriers of the CYP4F2 V433M allele have a reduced capacity to metabolize vitamin K. Secondary, this variant causes a decrease in steady-state hepatic concentrations of the enzyme.
    www.ncbi.nlm.nih.gov/pubmed/19297519
  • [Arteriosclerosis; Heart Diseases; Hemorrhage; Intracranial Hemorrhages; Myocardial Infarction; Peripheral Vascular Diseases; Pulmonary Embolism; Stroke; Thromboembolism; venous thromboembolism; Venous Thrombosis]
    [acenocoumarol]
    In a study of 100 white men with nonvalvular atrial fibrillation, the CYP4F2 rs2108622 (V433M) genotype significantly contributes to both early anticoagulant effect (international normalized ratio [INR]) (R2 = 0.14) and acenocoumarol dose requirements (R2 = 0.19). The V433M genotype had a gene dosage-dependent effect in decreasing plasma clotting factors in early drug response, with 433V homozygotes being the most sensitive. After initiation of therapy, the INR showed a gene significant dosage-dependent effect (P = .015), and 433V subjects needing 4 mg/week less than 433M carriers to achieve a steady anticoagulation (P = .043). The dose required to achieve a steady INR was also influenced by CYP4F2 genotype, similar to data reported for warfarin therapy. The CYP4F2 433M allele is reported to have decreased activity.
    www.ncbi.nlm.nih.gov/pubmed/19270263
  • [Arteriosclerosis; Heart Diseases; Hemorrhage; Intracranial Hemorrhages; Myocardial Infarction; Peripheral Vascular Diseases; Pulmonary Embolism; Stroke; Thromboembolism; venous thromboembolism; Venous Thrombosis]
    [acenocoumarol]
    Double homozygous VKORC1 1173T/T, CYP4F2 433Val/Val (n = 5) showed the highest INR (3.1; 2.0-4.7) and required the lowest acenocoumarol dose (11 ± 3 mg/week) The addition of the V433M genotype to the VKORC1 genotype raised the R2 from 8% to 14% for INR, and from 12% to 19% for acenocoumarol dose requirements.
    www.ncbi.nlm.nih.gov/pubmed/19270263
    PolyPhen-2
  • Score: 0.309 (possibly damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

"GENE" or "GENE A123C":

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