Genome-wide association study of abnormal elevation of ALT in patients exposed to atabecestat

Atabecestat, a potent brain penetrable BACE1 inhibitor that reduces CSF amyloid beta (A[beta]), was developed as an oral treatment for Alzheimer's disease (AD). Elevated liver enzyme adverse events were reported in three studies although only one case met Hy's law criteria to predict serious hepatotoxicity. We performed a case-control genome-wide association study (GWAS) to identify genetic risk variants associated with liver enzyme elevation using 42 cases with alanine transaminase (ALT) above three times the upper limit of normal (ULN) and 141 controls below ULN. Additionally, we performed a GWAS using continuous maximal ALT/ULN (expressed as times the ULN) upon exposure to atabecestat as the outcome measure (n = 285). No variant passed the genome-wide significance threshold (p = 5 x 10.sup.- 8) in the case-control GWAS. We identified suggestive association signals in genes (NLRP1, SCIMP, and C1QBP) implicated in the inflammatory processes. Among the genes implicated by position mapping using variants suggestively associated (p < 1 x 10.sup.- 5) with ALT elevation case-control status, gene sets involved in innate immune response (adjusted p-value = 0.05) and regulation of cytokine production (adjusted p-value = 0.04) were enriched. One genomic region in the intronic region of GABRG3 passed the genome-wide significance threshold in the continuous max(ALT/ULN) GWAS, and this variant was nominally associated with ALT elevation case status (p = 0.009). The suggestive GWAS signals in the case-control GWAS analysis suggest the potential role of inflammation in atabecestat-induced liver enzyme elevation.