Prospective study of ALDH1A1 gene polymorphisms associated with antituberculosis drug‐induced liver injury in western Chinese Han population

Abstract

Antituberculosis drug-induced liver injury (ATDILI) has received increasing attention globally, which may limit the effectiveness of antituberculosis (anti-TB) treatment. Many host genetic determinants of ATDILI have been identified recently. As little knowledge is currently available about the association between aldehyde dehydrogenase 1 family member A1 (ALDH1A1) polymorphisms and ATDILI, the association between their variants and the susceptibility to ATDILI was investigated. A total of 747 patients with TB treated by first-line anti-TB drugs were prospectively enrolled at West China Hospital. Genomic DNA was extracted from the peripheral blood sample of each patient and seven single-nucleotide polymorphisms (SNPs) of ALDH1A1 gene were screened and genotyped with a custom-designed 2×48-plex SNP Scan TM kit. The patients were followed up monthly to monitor the development of ATDILI. The C allele and the CA genotype of rs7852860 were significantly associated with an elevated risk for ATDILI (p = .006 and 0.005, respectively), which was consistent with the results in the dominant and additive models. No allele, genotype, or genetic model of the other six SNPs (rs3764435, rs348471, rs63319, rs610529, rs7027604, rs8187876) were found to be associated with susceptibility to ATDILI. The findings first demonstrate that rs7852860 variants in ALDH1A1 gene is associated with susceptibility to ATDILI in the Chinese Han population. Validation studies with larger sample sizes and other ethnic groups are needed to confirm the findings.

Genetic polymorphism related to ethambutol outcomes and susceptibility to toxicity

“…An additional 15% changed to the form of metabolites. EMB is partially inactivated by oxidation to an aldehyde intermediate, which is converted to the decarboxylic acid derivative assisted by a metabolic enzyme called aldehyde dehydrogenase 1 (ALDH1) ( Figure 2 ) ( PEETS et al, 1965 ; Peng et al, 2021 ). Other drug-metabolizing enzymes (DMEs), such as c ytochrome (CYP), also play a role in the metabolic rate of EMB.…”

“…Genetic polymorphisms can change the pharmacokinetic profile of EMB, such as creatinine clearance, plasma concentration, and drug exposure, and result in the possibility of toxicity or drug resistance ( Table 1 ). Genes that are included in this category are genes that encode ATP-binding cassette (ABC transporter), solute carrier family (SLC transporter), metabolizer enzymes; cytochrome (CYP), UDP-glucuronosyltransferase (UGT), aldehyde dehydrogenase (ALDH), glutathione S-transferase (GST), vitamin D receptor (VDR), pregnane X receptor (PXR), and genes related to optic neuropathy ( Takahashi et al, 2008 ; Ramachandran and Swaminathan, 2012 ; Fatiguso et al, 2016 ; Pontual et al, 2017 ; Sun et al, 2019 ; Peng et al, 2021 ) ( Figure 3 ).…”

“…The C allele and the CA genotype of rs7852860 were significantly associated with an elevated risk for ATDILI ( p = 0.006 and 0.005, respectively). Unfortunately, there were limitations of the study in that it was only conducted on Chinese people with a small number of samples ( Peng et al, 2021 ). Another gene related to the hepatotoxicity of EMB and the anti-TB regimen is UGT .…”

ALDH1A1 in Cancers: Bidirectional Function, Drug Resistance, and Regulatory Mechanism

“…Peng et al. demonstrated that rs7852860 variants of the ALDH1A1 gene were associated with susceptibility to anti-tuberculosis drug-induced liver injury ( 96 ).…”

Hepatic Adverse Effects of Anti-Mycobacterium Tuberculosis Drugs and Their Associations with Various Genetic Variants

“…CA genotype and C allele of rs7852860 were found notably associated with the risk of developing ATDILI. (Peng et al 2021)…”