GENETIC VARIANTS IN CYP2D6 AND THE PROPENSITY TO CHRONIC LIVER DISEASE IN MEN CHEWING KHAT

Introduction The chewing of the leaves of Catha edulis (khat) is widespread in Africa, Arabia and in the wider diaspora. Khat has been implicated in the development of chronic liver disease (CLD) but the determinants of susceptibility to its toxic effects are unknown. Genetic factors may play a role. Khat is metabolised in the liver via cytochrome P450 CYP2D6; genetic variants associated with low or null function, which may Result in khat accumulation, are possible candidates. In addition, variants in genes known to be associated with the development of other forms of CLD viz: PNPLA3:rs738409; TM6SF2:rs58542926 and MBOAT7:rs641738 could be implicated. Methods The study was undertaken in Harar, Ethiopia where khat chewing is wide-spread and the proportion of patients with ‘unexplained’ CLD exceeds 50%. The cases comprised of 120 khat-exposed hospital attendees (83% men) with CLD; the controls comprised of 195 khat-exposed attendees without CLD (68% men). Genotyping for single nuclear polymorphisms (SNPs) in CYP2D6 (rs1065852; rs3892097; rs28371706; rs28371725; rs59421388; rs61736512), PNPLA3:rs738409; TM6SF2:rs58542926 and MBOAT7:rs641738 was undertaken using KASPar on a RochLightCycler480. All genetic association tests were performed in PLINK v1.07. Results Significant associations were found, in men, between the risk of developing khat-related CLD and CYP2D6:rs3892097 (p=0.029; odds ratio (OR)=2.61 [95% confidence interval (CI) 1.1–6.2]) and CYP2D6:rs1065852 (p=0.039; OR=2.42 [95% CI 1.1–5.6]). These two SNPs are in close linkage disequilibrium (r2=0.8). The associations were not significant in women. No significant associations were identified between PNPLA3:rs738409, TM6SF2:rs58542926 and MBOAT7:rs641738 and either the overall or sex-specific risk of developing khat-related CLD. Conclusions Carriage of rs3892097 and rs1065852 in CYP2D6 is associated with an increase in the risk of developing khat-related CLD. The male specificity of this association is unexplained; more extensive exploration of CYP2D6 variants in population at risk is warranted.