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

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

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

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

Possible risk factors for the smear results at the end of intensive phase and anti- tuberculosis outcomes at the end of consolidation phase, respectively.

<p>IQR, inter-quartile range.</p>*<p>For the data of 51 patients missed, 4253 patients’ data were analyzed.</p>#<p>For the data of 16 patients missed, 4288 patients’ data were analyzed. Successful outcomes defined as the completion of treatment and patients being cured. Unsuccessful outcomes defined as treatment failure, default and death because of ADRs due to DOTS therapy.</p

Baseline Characteristics of 4304 Chinese tuberculosis patients.

<p>IQR, inter-quartile range.</p

Impact of ADRs due to directly observed treatment strategy therapy on smear results at the end of intensive phase and anti-TB treatment outcomes.

<p>ADRs, adverse drug reactions; TB, tuberculosis; OR, odds ratio; CI, confidence internal; AR%, attributable risk proportion; PAR%, population attributable risk proportion.</p><p>& A total of 518 patients developed ADRs within the intensive phase. For the data of 51 patients missed, 4253 patients’ data were analyzed.</p>$<p>A total of 649 patients developed ADRs at the end of anti-TB treatment. For the data of 16 patients missing, 4288 patients’ data was analyzed. Successful outcomes defined as the completion of treatment and patients being cured. Unsuccessful outcomes defined as treatment failure, default and death because of ADRs due to DOTS therapy.</p>*<p>Age, gender, TB treatment history and disease history were adjusted using logistic regression analysis.</p>§<p>Age, gender, TB treatment history and HBsAg status were adjusted using logistic regression analysis.</p>#<p>AR% and PAR% were calculated based on adjusted OR, respectively.</p

Causality assessment of adverse drug reactions due to directly observed treatment strategy therapy^*.

*<p>The causality assessment was done following the standards of WHO Uppsala Monitoring Center System by the experts from Center for Drug Reassessment of Chinese State Food and Drug Administration.</p>#<p>Data was presented as number of patients (%).</p