Roles of NR1I3 and NR1H4 polymorphisms in the susceptibility to antituberculosis drug-induced liver injury in China: a case‒control study

Xiaoyan Xu; Ruina Chen; Lihuan Lu; Jingru Cheng; Xiaomin He; Hongqiu Pan; Meiling Zhang; Honggang Yi; Shaowen Tang

doi:10.3389/fgene.2024.1428319

Roles of NR1I3 and NR1H4 polymorphisms in the susceptibility to antituberculosis drug-induced liver injury in China: a case‒control study

Front Genet. 2024 Oct 23:15:1428319. doi: 10.3389/fgene.2024.1428319. eCollection 2024.

Authors

Xiaoyan Xu¹, Ruina Chen², Lihuan Lu³, Jingru Cheng², Xiaomin He⁴, Hongqiu Pan⁵, Meiling Zhang⁶, Honggang Yi², Shaowen Tang²

Affiliations

¹ Department of Infectious Disease Control and Prevention, Changshu Center for Disease Control and Prevention, Suzhou, China.
² Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
³ Department of Tuberculosis, The Second People's Hospital of Changshu, Changshu, China.
⁴ Department of Infectious Disease, The People's Hospital of Taixing, Taixing, China.
⁵ Department of Tuberculosis, The Third People's Hospital of Zhenjiang Affiliated to Jiangsu University, Zhenjiang, China.
⁶ Department of Infectious Disease, The Jurong Hospital Affiliated to Jiangsu University, Jurong, China.

Abstract

Objective: The pathogenesis of antituberculosis drug-induced liver injury (AT-DILI) remains largely unknown. The current investigation aimed to determine the genetic contribution of the nuclear receptor subfamily 1 Group I member 3 (NR1I3) and nuclear receptor subfamily 1 Group H member 4 (NR1H4) genes to the risk of AT-DILI in the Chinese population.

Methods: A 1:4 matched case‒control study was conducted, and five single nucleotide polymorphisms (SNPs) in the NR1I3 and NR1H4 genes were detected and assessed. Utilizing a multivariate conditional logistic regression model, the effects of haplotype and genotype on the risk of AT-DILI were examined. Extended subgroup analysis was carried out based on sex. The distribution of the peak value of serum liver enzymes also compared among different genotypes.

Results: 224 AT-DILI cases and 896 controls were included in this study. No significant difference was observed in genotypes or haplotypes frequencies between AT-DILI cases and controls. However, comparisons of liver function indicators revealed significant differences in the peak values of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil) among patients with different genotypes of NR1H4 rs56163822 (GG vs. GT vs. TT, 27.1 U/L vs. 26.0 U/L vs. 23.0 U/L, p = 0.020; 34.0 U/L vs. 31.0 U/L vs. 30.6 U/L, p = 0.008; 15.5 μmol/L vs. 15.0 μmol/L vs. 13.7 μmol/L, p = 0.029, respectively), as well as in the peak values of ALT and AST among male patients with different genotypes of NR1H4 rs56163822 (29.0 U/L vs. 26.9 U/L vs. 22.6 U/L, p = 0.002; 34.0 U/L vs. 32.0 U/L vs. 30.5 U/L, p = 0.019, respectively).

Conclusion: Based on this 1:4 individual-matched case‒control study, the SNP rs56163822 in the NR1H4 gene may be linked to the susceptibility to AT-DILI in Chinese patients receiving anti-TB treatment. Further studies in larger varied populations are needed to validate our findings.

Keywords: antituberculosis drug-induced liver injury; case-control study; genetic polymorphisms; nuclear receptor subfamily 1 group H member 4; nuclear receptor subfamily 1 group I member 3.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was funded by a grant from the National Natural Science Foundation of China (grant no. 82073614) and Changshu Science and Technology Development Plan Project (grant no. CS202230).