Webinar 6: September 9th, 12.00-13.00 (SAST/CEST)

First talk:- Pharmacogenetics of fluoropyrimidine drugs: from discovery to clinical implementation

Speaker: Prof. Dr. Carlo Largiadèr (Department for Cllinical Chemistry, University of Bern)

Abstract: The fluoropyrimidines (FPs) 5-fluorouracil (5FU) and its oral prodrug capecitabine are among the most frequently used anticancer drugs. However, the occurrence of severe FP-related toxicities in 10-40% of the patients (depending on the treatment regimen) are an important drawback of these drugs, causing severe morbidity or treatment cessation. Reduced activity of DPD, the rate-limiting enzyme for 5-FU catabolism, is one of the main causes of FP-related toxicity and can partly be attributed to genetic variability in its encoding gene, DPYD. This genetic risk of toxicity after FP therapy has been studied for nearly four decades. Basic and clinical research on heritable DNA variation in the DPD gene variation (DPYD) has provided a wide range of knowledge, from in vitro function of genetic variants to cost evaluation of genetic testing in the clinic. However, despite the evidence for its clinical relevance, the implementation of DPYD pharmacogenetics into clinical practice has been slow. Recently, several European countries established pretreatment DPYD genotyping following the recommendation by the European Medicines Agency (EMA) in 2020.

Second talk:- Validation of HLA-II associations with tuberculosis susceptibility

Speaker: Dayna Croock (Division of Molecular Biology and Human Genetics, Stellenbosch University)

Abstract: The International Tuberculosis Host Genetics Consortium (ITHGC) demonstrated the power of large-scale GWAS analysis across diverse ancestries in identifying tuberculosis (TB) susceptibility loci. Despite identifying a significant genetic correlate in the human leukocyte antigen (HLA)-II region, this association did not replicate in the African ancestry-specific analysis. Possible reasons for the lack of replication included small sample size and the inclusion of admixed samples. Our study aimed to build upon the findings from the ITHGC and  identify TB susceptibility loci in an admixed South African cohort using the local ancestry allelic adjusted association (LAAA) model. We identified a near-genome-wide significant association (rs3117230, p-value = 5.292 x10-6, OR = 0.437, SE = 0.182) in the HLA-DPB1 gene originating from KhoeSan ancestry. These findings extend the work of the ITHGC, underscore the need for innovative strategies in studying complex admixed populations, and validate the role of the HLA-II region in TB susceptibility.

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