(275) CYP2C8 allele and genotype frequencies in adult Sickle Cell Disease Patients: implications for NSAIDs metabolism

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat prodromal signs of vasoocclusive pain in patients with sickle cell disease (SCD) are metabolized partly by the CYP2C8 enzyme. We determined the frequency of CYP2C8 alleles for the first time in adult African American SCD patients. Genomic DNA was isolated from blood samples of 165 patients aged between 18 and 61 years. Genotyping of seven CYP2C8 alleles (*1, *2, *3, *4, *5, *7 and *8) was performed using the iPlex ADME PGx panel and analyzed by iPlex Data Analysis Software. The CYP2C8*5,*7, and *8 alleles were not observed in our sample. The wild type *1 allele frequency was 0.806. The most common variant detected was the CYP2C8* 2 (0.164). The combined frequency of the *2, *3 and *4 variants was 0.194. The effects of CYP2C8*4 allele on substrate pharmacokinetics are unclear. In vitro data suggest that variant CYP2C8*2 and *3 alleles result in decreased metabolism of CYP2C8 substrates. However, in vivo data on the phenotypic consequences of these alleles have yielded contradictory results, problematizing assignment of extensive and intermediate predicted metabolic phenotypes (EM and IM) for some allelic combinations. We detected seven genotypes in our subjects as follows:*1/*1 (66.7%; EM), *1/*2 (24.2%; EM-IM), *1/*3 (2.4%; EM-IM), *1/*4 (1.2%; EM), *2/*2 (3.0%; IM), *2/*3 (1.2%; IM), and *1/*4 (1.2%;EM-IM). Our subjects had a disproportionately higher frequency of the CYP2C8*2 and *3 alleles in comparison to available CYP2C8 data for African Americans (0.182 vs. 0.110). This significant finding is similar to recent report that SCD patients had slightly higher frequency of the CYP2D6 gene deletion allele compared to healthy African Americans. Larger clinical studies should compare the frequency of impaired function alleles of CYP450 metabolic enzymes in SCD patients with other healthy African American groups to determine consequences on NSAIDs therapy and SCD pain phenotypes.