title: CYP2C9 allelic variants and frequencies in a pediatric sickle cell disease cohort: implications for NSAIDs pharmacotherapy.
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat pain in patients with sickle cell disease (SCD) are metabolized by the CYP2C9 enzyme. Racial differences in CYP2C9 allele frequencies impact NSAIDs efficacy and safety. We determined the frequencies of CYP2C9 alleles in an African American pediatric SCD cohort. Genomic DNA was isolated from blood samples of 30 patients aged between 7 and 17 years. Genotyping of nine CYP2C9 alleles (*1,*2, *3, *4, *5, *6, *8, *11, and *13) was performed using restriction fragment length polymorphism-PCR assays and the Tag-It™ Mutation Detection System. The wild type *1 allele frequency was 0.850. The most common variant allele detected was CYP2C9*8 (0.067). The combined frequency of the *2, *5, *6, *8, and *11 variants was 0.151. Seventy percent of the study cohort were predicted extensive metabolizers (*1/*1) and 30% were intermediate metabolizers due mainly to the *1/*8 genotype. Analysis of CYP2C9 using an expanded assay panel facilitated improved classification of predicted drug metabolic phenotypes in our cohort. However, the pharmacokinetic effects of the CYP2C9*5,*6,*8, and *11 alleles on NSAIDs metabolism has not been evaluated and underscores the need for studies on substrate-specific effects of variant alleles common in populations with genetic susceptibility to SCD.
authors.affiliation: College of Nursing, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Cheedy
authors.initials: C
authors.lastname: Jaja
authors.forename: Niren
authors.initials: N
authors.lastname: Patel
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Scott
authors.forename: Robert
authors.initials: R
authors.lastname: Gibson
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
mesh_terms: D000293:Adolescent; D000483:Alleles; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002648:Child; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D003710:Demography; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D005838:Genotype; D006801:Humans; D010641:Phenotype
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9
keywords: CYP2C9; NSAIDs; genotyping; pharmacogenetics; sickle cell disease