Dataset Information

Global variation in CYP2C8-CYP2C9 functional haplotypes.

ABSTRACT: We have studied the global frequency distributions of 10 single nucleotide polymorphisms (SNPs) across 132 kb of CYP2C8 and CYP2C9 in approximately 2500 individuals representing 45 populations. Five of the SNPs were in noncoding sequences; the other five involved the more common missense variants (four in CYP2C8, one in CYP2C9) that change amino acids in the gene products. One haplotype containing two CYP2C8 coding variants and one CYP2C9 coding variant reaches an average frequency of 10% in Europe; a set of haplotypes with a different CYP2C8 coding variant reaches 17% in Africa. In both cases these haplotypes are found in other regions of the world at <1%. This considerable geographic variation in haplotype frequencies impacts the interpretation of CYP2C8/CYP2C9 association studies, and has pharmacogenomic implications for drug interactions.

SUBMITTER: Speed WC

PROVIDER: S-EPMC2782405 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Global variation in CYP2C8-CYP2C9 functional haplotypes.

Speed William C WC Kang Soonmo Peter SP Tuck David P DP Harris Lyndsay N LN Kidd Kenneth K KK

The pharmacogenomics journal 20090421 4

We have studied the global frequency distributions of 10 single nucleotide polymorphisms (SNPs) across 132 kb of CYP2C8 and CYP2C9 in approximately 2500 individuals representing 45 populations. Five of the SNPs were in noncoding sequences; the other five involved the more common missense variants (four in CYP2C8, one in CYP2C9) that change amino acids in the gene products. One haplotype containing two CYP2C8 coding variants and one CYP2C9 coding variant reaches an average frequency of 10% in Eur ...[more]

PMID: 19381162

Similar Datasets

Project description:Background Genetic diversity of cytochrome P450 2C subfamily metabolizing epoxyeicosatrienoic acids, vasoactive substances with a wide range of biological actions in the cardiovascular system, contributes to the molecular basis of coronary artery disease (CAD). Association between genetic polymorphisms of CYP2C8, CYP2C9 and CYP2C19 and CAD risk has been extensively investigated in Chinese, Japanese, Korean and other Asian populations whereas a few studies have been done in Europeans. The present study investigated whether common single nucleotide polymorphisms (SNPs) of CYP2C8, CYP2C9 and CYP2C19 genes are important risk factors of CAD in a Russian population. Methods DNA samples from 1,255 unrelated subjects comprising 561 patients with angiographically diagnosed CAD and 694 age- and sex-matched healthy subjects were genotyped for six SNPs such as rs7909236, rs1934953 of CYP2C8, rs9332242, rs4918758 and rs61886769 of CYP2C9 and rs4244285 of CYP2C19 using by the Mass-ARRAY 4 system. Results SNP rs4918758 of CYP2C9 was associated with decreased risk of CAD with odds ratio 0.61 adjusted for sex and age (codominant genetic model, 95% CI: 0.41–0.92, P=0.038, Q =0.20). Log-likelihood ratio test pointed out epistatic interactions between SNPs rs9332242 and rs61886769 of CYP2C9 at a codominant genetic model (Pinteraction =0.02). Moreover, SNP rs9332242 of CYP2C9 showed a trend towards association with increased CAD risk in cigarette smokers (P=0.049, Q =0.29). Bioinformatic analysis using the SNP prediction tool revealed a regulatory potential for all SNPs associated with CAD. Conclusions To our knowledge, the present study is the first to show that polymorphisms rs4918758 and rs9332242 of CYP2C9 represent significant genetic markers of CAD susceptibility in Europeans. A validation of genetic markers associated with CAD risk in different races and ethnicities may cut corners between discovery and clinical qualification of such markers for the purposes of translational medicine. The study was supported by the Russian Science Foundation.

Project description:Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) widely used to alleviate pain and inflammation. Although it is generally considered safe, common adverse drug reactions of ibuprofen include stomach pain, nausea, and heartburn. It can also cause gastrointestinal (GI) bleeding, especially in individuals with a history of GI ulcers or bleeding disorders. Ibuprofen is predominantly metabolized by the cytochrome P450 (CYP) enzymes CYP2C9 and CYP2C8. Individuals carrying the CYP2C9∗3 or CYP2C8∗3 non-functional alleles have reduced enzyme activities resulting in elevated ibuprofen plasma concentrations and half-life. We presented a case of a 31-year-old Saudi female patient with a history of rheumatoid arthritis (RA) who had taken ibuprofen at 600 mg twice daily for eight weeks. The patient presented to the emergency department with symptoms including nausea, vomiting, severe abdominal pain, and black tarry stools. An emergency esophagogastroduodenoscopy was performed on the patient, which revealed a deep bleeding ulcer measuring 1 × 1 cm in the antrum of the stomach. Laboratory investigations indicated anemia (hemoglobin: 7.21 g/dL and hematocrit: 22.40 g/dl). The patient received intravenous proton pump inhibitors and a packed red blood cell transfusion. Genetic analysis revealed that the patient was a carrier of CYP2C9∗3 and CYP2C8∗3 variant alleles, indicating that the patient is a poor metabolizer for both enzymes. The patient's symptoms improved over the subsequent days, and she was discharged with instructions to avoid NSAIDs. This is the first reported Saudi patient homozygous for CYP2C9∗3 and CYP2C8∗3 variant alleles, which led to ibuprofen-induced upper GI toxicity. This case demonstrates the importance of contemplating CYP2C9 and CYP2C8 genetic variations when administrating NSAIDs like ibuprofen. Careful assessment of the risks and benefits of NSAID therapy in each patient and consideration of alternative pain management strategies must be conducted when appropriate.

Dataset Information

Global variation in CYP2C8-CYP2C9 functional haplotypes.

Publications

Global variation in CYP2C8-CYP2C9 functional haplotypes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets