Association of genetic variants of xenobiotic metabolic pathway with systemic lupus erythematosus.
In view of documented evidence that catechol estrogen-DNA adducts serve as epitopes for binding of anti-nuclear antibodies, genetic polymorphisms of the xenobiotic metabolic pathway involved in estrogen metabolism might contribute towards pathophysiology of systemic lupus erythematosus (SLE). To test this hypothesis, a case-control study was conducted. Cytochrome P 450 1A1 (CYP1A1) m4 (OR: 4.93, 95% CI: 1.31-18.49), catecholamine-o-methyl transferase (COMT) H108L (OR: 1.39, 95% CI: 1.03-1.88) and glutathione-S-transferase (GST) T1 null (OR: 1.83, 95% CI: 1.11- 3.01) variants showed association with SLE risk. SHEsis web-based platform analysis showed mild to moderate linkage disequilibrium between the CYP1A1 ml, m2 and m4 variants (D': 0.19-0.37). Among the different haplotypes of CYP1A1, CAC-haplotype harboring CYP1A1 ml variant showed association with SLE risk (OR: 1.46, 95% CI: 1.11-1.92). Multifactor dimensionality reduction analysis (MDR) showed potential gene-gene interactions between the phase II variants i.e. COMT H108L x GSTT1 null x GSTM1 null (p < 0.0001) and also between the phase II and I variants i.e. COMT H108L x GSTTI null x CYP1A1 ml x CYP1A1 m2 in inflating the risk of SLE by 3.33-folds (95% CI: 2.30-4.82) and 4.00-folds (95% CI: 2.77-5.78), respectively. To conclude, hyperinducibility of CYP1A1 due to ml and m4 variants and defective phase-II detoxification due to COMT H108L and GSTT1 null variants increase the susceptibility to SLE.
Yedluri
Y
Rupasree
Shaik Mohammad
SM
Naushad
Liza
L
Rajasekhar
Vijay Kumar
VK
Kutala
D000328:Adult; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D015262:Xenobiotics / Q000378:metabolism*
D015262:Xenobiotics