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

CYP2D6

The J1 haplotype, defined by the rs2267439 C>T variant located 285 kb downstream of CYP2D6, has been proposed as a modifier of phenotype prediction; phasing it with star alleles requires long-read sequencing because of its distance from the gene.

The authors used phased long-read sequencing data from 884 pediatric subjects to map the distribution of rs2267439, the variant defining the J1 haplotype, across CYP2D6 star alleles. The variant proved broadly distributed across alleles of all functional categories (normal, decreased and no function), without preferential co-segregation with any specific allele. The functional impact of the variants defining the J1, L and O1 haplotypes was then assessed by targeted genotyping in 125 Nigerian patients treated with risperidone: although highly prevalent in this cohort, none was associated with a significant difference in risperidone metabolic ratios across the CYP2D6*1/*1, *1/*2 or *1/*29 diplotype groups. The authors conclude that testing J1, L and O1 does not improve CYP2D6-based phenotype prediction for risperidone, and that incorporation into clinical guidelines would require validation across other populations and substrates.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A negative result worth knowing: it holds back the addition of a marker far from the gene to already complex panels, at a time when the Activity Score is criticised for its residual variability. The limitation is power, with 125 patients spread across three diplotype groups and a single substrate, which cannot exclude a modest effect. The long-read component has value of its own: showing that J1 does not mark any particular allele makes an effect confounded by haplotype structure unlikely.

Analysis by Dr Thibaut Benquey