Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs

Abstract

Background and aims: Drug-induced liver injury (DILI) is a serious adverse drug event that is suspected to have a heritable component. We carried out a genome-wide association study of 783 individuals of European ancestry who experienced DILI due to more than 200 implicated drugs.

Methods: DILI patients from the US-based Drug-Induced Liver Injury Network (n=401) and three international registries (n=382) were genotyped with the Illumina 1Mduo BeadChip and compared with population controls (n=3001). Potential associations were tested in 307 independent Drug-Induced Liver Injury Network cases.

Results: After accounting for known major histocompatibility complex risk alleles for flucloxacillin-DILI and amoxicillin/clavulanate-DILI, there were no genome-wide significant associations, including in the major histocompatibility complex region. Stratification of DILI cases according to clinical phenotypes (injury type, latency, age of onset) also did not show significant associations. An analysis of hepatocellular DILI (n=285) restricted to 193 single-nucleotide polymorphisms previously associated with autoimmune disease showed a trend association for rs7574865, in the vicinity of signal transducer and activator of transcription 4 (STAT4) (P=4.5×10(-4)). This association was replicated in an independent cohort of 168 hepatocellular DILI cases (P=0.011 and 1.5×10(-5) for combined cohorts). No significant associations were found with stratification by other clinical or demographic variables.

Conclusion: Although not significant at the genome-wide level, the association between hepatocellular DILI and STAT4 is consistent with the emerging role of the immune system in DILI. However, the lack of genome-wide association study findings supports the idea that strong genetic determinants of DILI may be largely drug-specific or may reflect rare genetic variations, which were not assessed in our study.

Fig. 1

Manhattan and Quantile–quantile plots of association study results including (a, d) or excluding (b, e) drug-induced liver injury (DILI) cases due to amoxicillin/clavulanate or flucloxacillin, for which strong genetic risk variants in the MHC region have been identified previously [7]. The genome-wide association study was also carried out including all cases, but conditioned on the known major histocompatibility complex single-nucleotide polymorphisms associated with flucloxacillin-induced or amoxicillin/clavulanate-induced DILI (c, f). The Manhattan plot shows the location along the genome on the x-axis and the –log₁₀ P-value along the x-axis. A P-value less than 10⁻⁸ was considered significant. The quantile–quantile plot shows in rank order the observed P-values versus those expected under the null hypothesis, showing adequate correction for population structure (genomic inflation factor, λ = 1.02) and significant deviation from the null for the top-associated SNPs only in the analysis including amoxicillin/clavulanate and flucloxacillin cases.

Fig. 2

Power estimates for the identification of drug-induced liver injury risk variants given available sample sizes. (a) Power versus sample size over a range of relative risk, assuming a minor allele frequency of 0.05, sample size: n = 783 cases versus n = 3000 controls, population prevalence of 1 : 10 000, and significance threshold P < 10⁻⁸. (b) Detectable relative risk (RR) versus risk allele frequency over a range of power (1 – β), assuming r² = 1 between the marker and the causal risk allele, and sample sizes and significance threshold as above.

Fig. 3

Manhattan (a) and Quantile–quantile (b) plots of genome-wide association study results for the analysis of all drug-induced liver injury (DILI) cases including flucloxacillin, but excluding amoxicillin/clavulanate-induced DILI cases. Despite the fact that flucloxacillin-DILI cases make up only 13.4% of the total case sample (75/560), there remains clear evidence of an HLA-B*5701 (rs2395029) association with DILI risk in the combined sample, suggesting that misclassification or heterogeneity of cases is unlikely to obscure the true DILI risk variants of a very large effect (the HLA-B*5701 allele confers an 80-fold increased risk of DILI from flucloxacillin [7]).