Gender-Dimorphic Impact of PXR Genotype and Haplotype on Hepatotoxicity During Antituberculosis Treatment. Issue 24 (June 2015)

• Record Type: Journal Article
• Authors: Wang, Jann Yuan; Tsai, Ching Hui; Lee, Yungling Leo; Lee, Li Na; Hsu, Chia Lin; Chang, Hsiu Ching; Chen, Jong Ming; Hsu, Cheng An; Yu, Chong Jen; Yang, Pan Chyr; Naranbhai., Vivek
• Is Part Of: Medicine. Volume 94:Issue 24(2015)
• Publication Date: 2015-06
• Subjects: Medicine -- Periodicals; Medicine -- Periodicals; Médecine -- Périodiques; Geneeskunde; Medicine; Periodicals; Periodicals; 610.5
• DOI: 10.1097/MD.0000000000000982
• Languages: English
• ISSNs: 0025-7974

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Abstract</title> <p>Women have a higher risk of drug-induced hepatotoxicity during antituberculosis treatment (HATT) than men. We hypothesized that single nucleotide polymorphism (SNP) genotype and derived haplotype of <italic>pregnane X receptor</italic> (<italic>PXR</italic>) gene, which could regulate the expression of phase I enzyme cytochrome P450 (CYP) 3A4, had a sex-specific influence on the risk of HATT.</p> <p>Six SNPs of the <italic>PXR</italic> gene were sequenced. Genotypes and haplotypes of the <italic>PXR</italic> SNPs, and other potential risk factors for HATT were compared between pulmonary TB patients with and those without HATT. HATT was defined as an increase in serum transaminase level >3 times the upper limit of normal (ULN) with symptoms, or >5 times ULN without symptoms. We performed the study in a derivation and a validation cohort.</p> <p>Among the 355 patients with pulmonary TB in the derivation cohort, 70 (19.7%) developed HATT. Logistic regression analysis revealed the risk of HATT increased in female genotype AA at rs2461823 (OR: 6.87 [2.55–18.52]) and decreased in female genotype AA at rs7643645 (OR: 0.14 [0.02–1.02]) of <italic>PXR</italic> gene. Haplotype analysis showed that female h001101 (OR: 2.30 [1.22–4.32]) and female h000110 (OR: 2.25 [1.08–4.69]) haplotype were associated with increased HATT risk. The identified predictors were also significantly associated with female HATT risk among the 182 patients in the validation cohort.</p> <p>Two <italic>PXR</italic> SNP genotypes and 2 haplotypes influenced the risk of HATT only in females. The <italic>PXR</italic> SNP showed a sex-specific impact that contributed to an increased HATT risk in females.</p> </sec> </abstract>