Genetic risk factors in drug-induced liver injury due to isoniazid-containing anti-tuberculosis drug regimens.

Drug-induced liver injury (DILI) is a complication of treatment with anti-tuberculosis (TB) drugs, especially in isoniazid-containing regimens. To investigate genetic risk factors, we performed a genome-wide association study (GWAS) involving anti-TB DILI cases (55 Indian, 70 European) and controls (1199 Indian, 10397 European). Most cases were treated with a standard anti-TB drug regimen; all received isoniazid. We imputed single nucleotide polymorphism and HLA genotypes and performed trans-ethnic meta-analysis on GWAS and candidate gene genotypes. GWAS found one significant association (rs117491755) in Europeans only. For HLA, HLA-B*52:01 was significant (meta-analysis odds ratio (OR) 2.67; 95%CI 1.63-4.37; P=9.4x10-5 ). For N-acetyltransferase 2 (NAT2), NAT2*5 frequency was lower in cases (OR 0.69; 95%CI 0.57-0.83, P=0.01). NAT2*6 and NAT2*7 were more common, with homozygotes for NAT2*6 and/or NAT2*7 enriched among cases (OR 1.89; 95%CI 0.84-4.22; P=0.004). We conclude HLA genotype makes a small contribution to TB drug-related DILI and that the NAT2 contribution is complex, but consistent with previous reports when differences in the metabolic effect of NAT2*5 compared with those of NAT2*6 and NAT2*7 are considered