Analysis of IL-6, STAT3 and HSPA1L Gene Polymorphisms in Anti-Tuberculosis Drug-Induced Hepatitis in a Nested Case-Control Study

<div><p>Objectives</p><p>To investigate the association of IL-6, STAT3 and HSPA1L polymorphisms with the risk of anti-tuberculosis drug-induced hepatitis (ATDH) in Chinese Han population.</p><p>Methods</p><p>The study was designed as a nested case-control study within a prospective cohort. Each case was matched with four controls by sex, age at baseline (±5 years), treatment history, disease severity, drug dosage and place of sample collection. Genetic polymorphisms of IL-6, STAT3 and HSPA1L were determined blindly by TaqMan single-nucleotide polymorphism (SNP) genotyping assay. Odds ratio (OR) with 95% confidence intervals (CIs) was estimated by conditional logistic regression model to measure the association between selected SNPs and the risk of ATDH.</p><p>Results</p><p>A total of 89 incident ATDH cases and 356 ATDH-free controls were genotyped for IL-6 (rs2066992, rs2069837, rs1524107), STAT3 (rs1053004, rs1053023, rs1053005) and HSPA1L (rs2227956). In genotype analysis, no significant difference was observed in genotypes frequencies of the seven selected SNPs between case and control group after Bonferroni correction. In haplotype analysis, carriers with STAT3 GAT and AGC (rs1053023-rs1053005-rs1053004) haplotypes had a significantly higher risk of ATDH compared with wild-type haplotype (P<0.0001).</p><p>Conclusion</p><p>This study suggested that genetic variants of STAT3 might contribute to ATDH susceptibility in Chinese Han population. Studies in larger, varied populations are required to confirm these findings.</p></div

Cytochrome P450 2E1 Gene Polymorphisms/Haplotypes and Anti-Tuberculosis Drug-Induced Hepatitis in a Chinese Cohort

<div><p>Objective</p><p>The pathogenic mechanism of anti-tuberculosis (anti-TB) drug-induced hepatitis is associated with drug metabolizing enzymes. No tagging single-nucleotide polymorphisms (tSNPs) of cytochrome P450 2E1(CYP2E1) in the risk of anti-TB drug-induced hepatitis have been reported. The present study was aimed at exploring the role of tSNPs in <i>CYP2E1</i> gene in a population-based anti-TB treatment cohort.</p> <p>Methods and Design</p><p>A nested case-control study was designed. Each hepatitis case was 14 matched with controls by age, gender, treatment history, disease severity and drug dosage. The tSNPs were selected by using Haploview 4.2 based on the HapMap database of Han Chinese in Beijing, and detected by using TaqMan allelic discrimination technology.</p> <p>Results</p><p>Eighty-nine anti-TB drug-induced hepatitis cases and 356 controls were included in this study. 6 tSNPs (rs2031920, rs2070672, rs915908, rs8192775, rs2515641, rs2515644) were genotyped and minor allele frequencies of these tSNPs were 21.9%, 23.0%, 19.1%, 23.6%, 20.8% and 44.4% in the cases and 20.9%, 22.7%, 18.9%, 23.2%, 18.2% and 43.2% in the controls, respectively. No significant difference was observed in genotypes or allele frequencies of the 6 tSNPs between case group and control group, and neither of haplotypes in block 1 nor in block 2 was significantly associated with the development of hepatitis.</p> <p>Conclusion</p><p>Based on the Chinese anti-TB treatment cohort, we did not find a statistically significant association between genetic polymorphisms of <i>CYP2E1</i> and the risk of anti-TB drug-induced hepatitis. None of the haplotypes showed a significant association with the development of hepatitis in Chinese TB population.</p> </div

ORs and 95% CIs for ATDH in relation to IL-6 and STAT3 haplotypes.

<p>^a Conditional logistic regression model analysis.</p><p>^b Significant after Bonferroni correction for multiple comparisons.</p><p>ORs and 95% CIs for ATDH in relation to IL-6 and STAT3 haplotypes.</p

Distribution of genotypes in patients with and without anti-TB drug-induced hepatitis.

a<p>conditional logistic regression model analysis.</p>b<p>Dom, dominant model; Rec, recessive model; Add, additive mode.</p

Characteristics of patients with and without ATDH.

<p>BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate aminotransferase.</p><p>^a Values are presented as mean ± SD</p><p>^b Normal intervals: ALT<40 U/L, AST<40 U/L, Total bilirubin<19 umol/L.</p><p>^c Values are presented as median (inter-quartile range).</p><p>Characteristics of patients with and without ATDH.</p

Haplotype frequencies and the risks of anti-TB drug-induced hepatitis.

a<p>conditional logistic regression model analysis.</p

Information on six genotyped tSNPs of the CYP2E1 gene.

†<p>SNP position in NCBI dbSNP (<a href="http://www.ncbi.nlm.nih.gov/projects/SNP" target="_blank">http://www.ncbi.nlm.nih.gov/projects/SNP</a>).</p>‡<p>Minor allele frequency (MAF) for Han Chinese in Beijing in the HapMap database (<a href="http://www.hapmap.org" target="_blank">http://www.hapmap.org</a>).</p>*<p>Hardy–Weinberg equilibrium (HWE) <i>P</i>-value in the control group.</p

Characteristics of patients with and without anti-TB drug-induced hepatitis.

*<p>Normal intervals: ALT<40U/L, AST<40U/L, Total bilirubin<19 umol/L.</p><p>BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate aminotransferase.</p>†<p>Values are presented as mean±standard deviations (range).</p>‡<p>Values are presented as median (inter-quartile range).</p>§<p>two-factor analysis of variance test.</p>¶<p>Median test.</p

IL-6, STAT3 and HSPA1L Polymorphisms in Patients with and without ATDH.

<p>^a Conditional logistic regression model analysis.</p><p>IL-6, STAT3 and HSPA1L Polymorphisms in Patients with and without ATDH.</p

Incidence, onset time and seriousness of adverse drug reactions due to directly observed treatment strategy therapy in 4304 Chinese tuberculosis patients.

<p>IQR, inter-quartile range.</p>#<p>The incidence of ADR was standardized for age and gender with direct standardization using one reference population that from national TB epidemic surveillance database of 2008.</p>†<p>It was from initiation of treatment.</p>§<p>Serious ADRs were defined as any untoward medical occurrence that at any dose results in death, requires hospital admission or prolongation of existing hospital stay, results in persistent or significant disability/incapacity, or is life threatening.</p>$<p>It was the time that ADRs were found, not the exact time it happened.</p>‡<p>Nervous system disorders included auditory nerve damage, optic nerve damage, peripheral nervous damage and central nervous system damage.</p>€<p>Others included one with interstitial pneumonia and another with hypokalemia.</p>*<p>For 82 patients got two ADRs, sixteen got three and one got four, 766 cases were detected and the denominator was 4304+82+32+3 = 4421.</p