Association of POR and PPARα polymorphisms with risk of anti-tuberculosis drug-induced liver injury in Western Chinese Han population

Abstract

Objectives: Anti-tuberculosis drug-induced liver injury (ATDILI) is a common and sometimes severe adverse drug reaction (ADR). This study was conducted to investigate the relationship between polymorphisms of two genes, cytochrome P450 oxidoreductase (POR) and peroxisome proliferator-activated receptor α (PPARα), and the risk of ATDILI in Western Chinese Han population.

Methods: A total of 118 tuberculosis (TB) patients with ATDILI and 628 TB patients without ATDILI during anti-TB treatment were recruited from West China Hospital of Sichuan University. DNA was extracted from peripheral blood, and genotypes of the selected 12 single nucleotide polymorphisms (SNPs) (3 SNPs in the POR gene and 9 SNPs in the PPARα gene) were determined. Three genetic models (additive, dominant, and recessive), as well as a haplotype, were used to test the genetic risk of ATDILI. Extended subgroup analysis was conducted according to age, sex and different causality assessments.

Results: The mutant allele, genotype and genetic model of rs3898649 in the POR gene were found to be associated with increased risk of ATDILI, especially in the younger (<50 years old), female and pulmonary tuberculosis subgroup. The other two SNPs rs28737229 and rs4728533 in the POR gene showed only a potential association with susceptibility to ATDILI after Bonferroni correction (P < .05 but P_Bonferroni > .05). The other 9 SNPs loci (rs135549, rs9626730, rs4253712, rs4823613, rs4253730, rs6007662, rs4253728, rs2024929 and rs135561) in the PPARα gene showed no significant differences between ATDILI and non-ATDILI in either allele frequencies or genotype (all P >.05).

Conclusions: The results demonstrated the strong correlation between POR gene SNP rs3898649 and ATDILI susceptibility, suggesting the importance of POR rs3898649 in the pathogenesis and development of ATDILI. Therefore, our results indicated that POR rs3898649 might be a valuable biomarker potentially involved in ATDILI.

Keywords: Anti-tuberculosis drug; Liver injury; P450 oxidoreductase (POR); Peroxisome proliferator-activated receptor α (PPARα, or NR1C1); Polymorphism.