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Identification of a Functional CYP2C8 Variant Allele that Alters Splicing, Reduces Protein Expression, and Increases
Anssi J H Mykkänen1,2,3, Päivi Hirvensalo1,3,4, Kathrin Klein5,6
1Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
Abstract:
This study investigated genetic determinants of the pharmacokinetics of the CYP2C8 index drugs repaglinide and gemfibrozil, and their interaction in healthy participants. Sequencing data from a study with montelukast revealed a novel functional CYP2C8 allele (rs2071426, CYP2C8*19), predicted to create an intronic splice donor site. In human liver samples, CYP2C8*19 associated with transcript-specific changes in CYP2C8 mRNA expression, reduced CYP2C8 protein expression, and decreased enzyme activity. Consistently, participants with the CYP2C8*19/*19 genotype had 45% greater area under the plasma repaglinide concentration-time curve from time zero to infinity (AUC0-∞) than participants with CYP2C8*1/*1 (P = 1.6 × 10-4). Participants with CYP2C8*1/*3 had 26% smaller AUC0-∞ (P = 0.0033) and those with CYP2C8*1/*4 had 51% greater AUC0-∞ (P = 8.2 × 10-4). The fold increase in repaglinide AUC0-∞ caused by gemfibrozil was 36% (P = 1.3 × 10-4) smaller in CYP2C8*19/*19 participants than in CYP2C8*1/*1 participants. In a genome-wide association study (GWAS), SLCO1B1 c.521 T>C (rs4149056) associated with increased repaglinide AUC0-∞ (P = 4.5 × 10-15; n = 172) and SLCO1A2 variants associated with decreased AUC0-∞ (P < 10-8). In a GWAS of repaglinide after gemfibrozil pretreatment, SLCO1C1 variants associated with decreased AUC0-∞ (P < 1.6 × 10-8; n = 66). Participants with the poor function SLCO1B1 genotype showed a 32% smaller fold increase in repaglinide AUC0-∞ following gemfibrozil than participants with the normal function SLCO1B1 genotype (P = 0.0045). This study characterizes CYP2C8*19 as a novel decreased function allele and shows that CYP2C8 and SLCO1B1 genotypes affect the gemfibrozil-repaglinide interaction.
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