Association of LEPR polymorphisms with predisposition and inflammatory response in anti-tuberculosis drug-induced liver injury: A pilot prospective investigation in Western Chinese Han population

Abstract

Objectives: Previous studies have proposed leptin/leptin receptor (LEPR) pathway has a potential role in the oxidative stress induction as well as in immune and inflammatory responses; however, the effects of leptin/LEPR signaling on anti-tuberculosis drug-induced liver injury (ATLI) remain unexplored. Here, we aimed to investigate the potential relationships between LEPR polymorphisms and ATLI risk and clinical characteristics.

Methods: In total, this prospective study included 745 tuberculosis subjects with isoniazid and rifampin co-administration from West China. Six candidate single nucleotide polymorphisms (SNPs) in LEPR gene were genotyped by using a custom-by-design 48-Plex SNPscan kit. All subjects were monitored for six months to assess the occurrence of ATLI. Genetic association analysis at both the single-SNP and haplotype levels was performed. Significant SNPs were further explored in relation to clinical features and inflammatory response of ATLI cases.

Results: ATLI was identified in 118 of 745 subjects with a prevalence rate of 15.84%. Significant differences were observed in the allele and genotype distribution of LEPR rs2025804 in ATLI cases compared to non-ATLI controls (allele: OR = 1.64, 95% CI = 1.15-2.32, adjusted-p = .036; dominant model: OR = 1.73, 95% CI = 1.14-2.61, adjusted-p = 0.054; additive model: OR = 1.64, 95% CI = 1.15-2.34, adjusted-p = 0.036). Haplotype AA comprising of rs2025804 and rs2104564 was associated with a 1.58-fold increased predisposition to ATLI with p = 0.013. Furthermore, among ATLI patients, individuals carrying minor allele-containing genotypes in rs10889551, rs2025804 and rs2104564 loci had higher levels of C-reactive protein as compared to those homozygous major allele carriers, at p of 0.002, 0.057 and 0.012, respectively.

Conclusion: Ours is the first study which shows that LEPR polymorphisms may increase the risk for ATLI and may influence the inflammatory response in ATLI patients among Western Chinese Han tuberculosis patients.

Keywords: Anti-tuberculosis drug-induced liver injury (ATLI); Inflammatory response; Leptin receptor (LEPR); Polymorphisms; Predisposition.