#6812 ON THE TOP PHARMACOGENETICS STUDY EXTRACTED FROM EXOME SEQUENCING DONE FOR CHRONIC KIDNEY DISEASES OF UNKNOW ORIGIN

Abstract

Abstract Background and Aims A recent study from a large cohort published by the Ubiquitous Pharmacogenomic Consortium demonstrates the interest of pre-emptive pharmacogenetic panel testing, with a 30% reduction rate of clinically detectable side-effects. Our laboratory routinely performs diagnostic exome sequencing (ES) for adult patient with kidney disease and more than 2000 patients have been analyzed to date. Patient with chronic kidney diseases (CKD) could benefit from pharmacogenetics information, since they are often polymedicated and efficacy or safety of their medications are known to be influenced by the genetic background. We studied if meaningful pharmacogenetics information could be delivered from exome sequencing data provided for CKD, either retrospectively or prospectively. Method We selected 214 variants of pharmacogenetics relevance, based on evidence and frequency criteria. We evaluated their depth of coverage on 300 patients randomly selected in our CKD cohort. Results Eleven of those 214 variants were not covered by ES. Three of 11 variants were in UGT1A1 and were excluded from analysis since this information is only relevant for Irinotecan treatment. The remaining 8 variants fall in CYP2C19, CYP3A5, CYP3A4, CYP2D6, HLA B (B15:02), HLA A (A31:01), IFNL3, VKORC1 genes: we completed exome data by targeted sanger sequencing for these variants. One challenging region is CYP2D6 given high sequence homology with CYP2D7 and CYP2D8: to assess if we could reliably call variants in this region, we used 7 additional Coriell samples, as 8 others were also assessed with an orthogonal technique. We were able to properly detect variants in these complex regions in all cases, including hybrid genes. Conclusion Our preliminary data show that exome sequencing, initially ordered for CKD, could also be used to deliver pharmacogenetic meaningful information, by adding a few targeted genotyping assays. We currently evaluate the clinical utility and impact of pharmacogenetics in our CKD cohort prospectively.