Abstrait

Failure to replicate a previously reported GWAS association between KCNJ1 gene and co-amoxiclav-induced liver injury

Mohammad A. Alshabeeb

Background: Co-amoxiclav is associated with Drug-Induced Liver Injury (DILI). HLA genotype is an important predictor of DILI susceptibility but it is likely that non-HLA risk factors also contribute. This study aimed to characterize non-HLA risk factors in larger cohorts than previously. Although KCNJ1 is known for its regulation of kidney activities through modulation of potassium homeostasis, the association seen between this gene and co-amoxiclav DILI, detected in a previous Genome-Wide Association Study (GWAS), which was close to p-value threshold significance, was stimulating to investigate its role in DILI susceptibility. Methods: A variant (rs2855790) in KCNJ1 was genotyped to extend the previous findings. 73 coamoxiclav adjudicated DILI cases and 75 community controls were genotyped using RFLP-PCR assay. Drug causality of the cases was assessed using the RUCAM method. The data obtained were analyzed for its Odds Ratio (OR) value and Fisherâ??s exact test was used to generate a p-value. Results: Although, variant allele frequency in cases were much lower (15.8%) than in controls (24.7%); however, the difference was not statistically significant (OR=0.58, 95% CI=0.29-1.1; P=0.13). Hence, the previously reported association with KCNJ1 (rs2855790) could not be confirmed in this new cohort of co-amoxiclav DILI. Conclusion: Given the biological role of KCNJ1 in the kidney, not the liver, this gene was not a very biologically plausible candidate as a DILI gene so the final result obtained for this is not too surprising.