A Genome-Wide Association Study of Antituberculosis Drugs-Induced Hepatitis

Backgrounds: Antituberculosis drugs (ATD) are the major causes of drug-induced liver injury (DILI). Although genetic factors are known to play a role in the development of ATD-induced hepatitis, the genetic susceptibility to this condition is poorly understood yet.

Methods: We performed a genome-wide association study (GWAS) to identify the genetic variants associated with the risk of ATD-induced hepatitis in a Korean population. DNA obtained from 40 patients with ATD-induced hepatitis and 119 ATD-tolerant subjects were genotyped on Affymetrix Genome-Wide Human SNP Array 6.0. After identification of genetic variants with significant associations, gene set enrichment analysis was done to find the relevant pathways associated with ATD-induced hepatitis.

Results: In the case-control analysis, we found significant genetic variants at ID2 (rs345904, P=4.06 x 10^-7, OR 8.03, 95% CI 3.34-19.35), PLXNA4 (rs156978, P=8.48 x 10^-6, OR 12.78, 95% CI 3.31-49.36) and ZNF804B (rs2718306, P=8.26 x 10^-6, OR 10.72, 95% CI 3.18-36.11). Pathway analysis identified several pertinent pathways including axon guidance, cGMP effects, developmental biology, signaling by Rho GTPases and interaction between L1 and ankyris.

Conclusions: This GWAS identified genetic variants and pathways underlying the development of ATD-induced hepatitis. These results provides insights into the genetic susceptibility to ATD-induce hepatitis.