Distribution of the J1 haplotype variant rs2267439 across CYP2D6 diplotypes and its impact on risperidone metabolism

CYP2D6 is a highly polymorphic pharmacogene responsible for the metabolism of more than 20% of commonly prescribed drugs. Clinical implementation of CYP2D6 pharmacogenetics relies on star allele nomenclature and the Activity Score system, yet substantial interindividual variability in drug exposure remains unexplained. A recent study proposed that the so-called J1 haplotype, defined by rs2267439 C>T located 285 kb downstream of CYP2D6, improves phenotype prediction when combined with revised activity values for selected alleles. However, accurate resolution of the phase of the J1 variant with star alleles requires long-read sequencing due to the distant genomic location of rs2267439 from the gene. In this study, we used phased long-read sequencing data from 884 pediatric subjects to characterize the distribution of the J1-defining variant across CYP2D6 star alleles. Additionally, we evaluated the functional impact of the variants defining the J1, L, and O1 unphased haplotypes on risperidone metabolism in a Nigerian cohort of 125 patients treated with risperidone using targeted genotyping. Phased long-read sequencing revealed that the J1/rs2267439 variant is broadly distributed across CYP2D6 star alleles of all functional categories (normal, decreased, and no function) without preferential co-segregation with any specific allele. In the risperidone-treated African unphased cohort, J1, L, and O1-defining variants were highly prevalent, yet none were associated with statistically significant differences in risperidone metabolic ratios across CYP2D6*1/*1, *1/*2, or *1/*29 diplotype groups. These findings suggest that testing the J1, L, and O1-defining variants may not improve CYP2D6-based phenotype prediction for risperidone. Incorporation of these variants into clinical guidelines requires further validation across diverse populations and multiple substrates.