CYP2C8 R139K - GET-Evidence

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

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Curation:
Currentness:

CYP2C8 R139K

(CYP2C8 Arg139Lys)


Short summary

 

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

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr10:96827030: 8.7% (931/10758) in EVS
  • T @ chr10:96817019: 7.8% (10/128) in GET-Evidence
  • Frequency shown in summary reports: 8.7% (931/10758)

Publications
 

Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI, Goldstein JA. Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics. 2001 Oct;11(7):597-607. PubMed PMID: 11668219.

 

Yasar U, Bennet AM, Eliasson E, Lundgren S, Wiman B, De Faire U, Rane A. Allelic variants of cytochromes P450 2C modify the risk for acute myocardial infarction. Pharmacogenetics. 2003 Dec;13(12):715-20. PubMed PMID: 14646690.

 

Bozkurt O, de Boer A, Grobbee DE, Heerdink ER, Burger H, Klungel OH. Pharmacogenetics of glucose-lowering drug treatment: a systematic review. Mol Diagn Ther. 2007;11(5):291-302. Review. PubMed PMID: 17963417.

 

Gil JP. Amodiaquine pharmacogenetics. Pharmacogenomics. 2008 Oct;9(10):1385-90. Review. PubMed PMID: 18855526.

 

Leskelä S, Jara C, Leandro-García LJ, Martínez A, García-Donas J, Hernando S, Hurtado A, Vicario JC, Montero-Conde C, Landa I, López-Jiménez E, Cascón A, Milne RL, Robledo M, Rodríguez-Antona C. Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity. Pharmacogenomics J. 2011 Apr;11(2):121-9. Epub 2010 Mar 9. PubMed PMID: 20212519.

 

Genomes
 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het T @ chr10:96827030

 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
hom T @ chr10:96827030

 

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het T @ chr10:96827030

 

hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
het T @ chr10:96827030

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
hom T @ chr10:96827030

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het T @ chr10:96827030

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
hom T @ chr10:96827030

 

GS06994 - var-GS06994-1100-36-ASM
het T @ chr10:96817020

 

Other external references
 

    dbSNP
  • rs11572080
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [paclitaxel]
    The variant is part of the CYP2C8*3 allele. In in vitro studies, the recombinant expressed CYP2C8*3 exhibits markedly impaired metabolism of paclitaxel and arachidonic acid.
    www.ncbi.nlm.nih.gov/pubmed/11668219
  • [repaglinide; rosiglitazone]
    Different literature sources show a discrepancy between several in vitro findings describing a lower activity of the CYP2C8*3 variant and in vivo findings showing higher oral clearance in *3 allele carriers at last for some substrates ofCYP2C8. A study on healthy volunteers administered with repaglinide found that the CYP2C8*3 variant allele was associated with reduced plasma conentrations of repaglinde. Another study showed that subjects carrying the CYP2C8*3allele had a lower rosiglitazone plasma concentartion.
    www.ncbi.nlm.nih.gov/pubmed/14534525; PubMed ID:17178266
  • [Malaria]
    [amodiaquine]
    CYP2C8*3 has no detectable amodiaquine metabolism activity in vitro.
    www.ncbi.nlm.nih.gov/pubmed/18855526
  • [Diabetes Mellitus, Type 2]
    CYP2C8*3 allele (containing Arg139Lys and Lys399Arg) is associated with increased the clearance of meglitinides.
    www.ncbi.nlm.nih.gov/pubmed/17963417
  • [Myocardial Infarction]
    Risk or phenotype-associated allele: A. Phenotype: In woman, the risk of acute myocardial infarction (AMI) tended to be higher for subjects carrying the CYP2C8*3*3 genotype versus *1*1 (OR = 1.9). The CYP2C8*3 variants are 416G>A (rs10509681) and 1196A>G (rs11572080). Tested in all subjects, the risk of AMI was also higher in individuals carrying the CYP2C8*3 allele (*3*3; *1*3 versus*1*1) [1.2 (1.0-1.5), P = 0.07]. Study size: 1172 AMI patients and 1503 control subjects. Study population: Caucasian.
    www.ncbi.nlm.nih.gov/pubmed/14646690
  • [Drug Toxicity; Neurotoxicity Syndromes]
    [paclitaxel]
    Risk or phenotype-associated allele: A. Phenotype: This variant was associated with increased risk for neurotoxicity with paclitaxel treatment. Study size: 132. Study population/ethnicity: Patients with Neoplasms receiving paclitaxel; Spain. Significance metric(s): HR = 1.54 (0.96-2.47); p = 0.072. Type of association: PK; TOX.
    www.ncbi.nlm.nih.gov/pubmed/20212519
    PolyPhen-2
  • Score: 0.015 (benign)

Other in silico analyses
 

  • NBLOSUM100 score = –3
  • GET-Evidence autoscore = 1

Edit history
 

Gene search

"GENE" or "GENE A123C":

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