title: Application of Various Statistical Models to Explore Gene-Gene Interactions in Folate, Xenobiotic, Toll-Like Receptor and STAT4 Pathways that Modulate Susceptibility to Systemic Lupus Erythematosus.
abstract: BACKGROUND
  In view of our previous studies showing an independent association of genetic polymorphisms in folate, xenobiotic, and toll-like receptor (TLR) pathways with the risk for systemic lupus erythematosus (SLE), we have developed three statistical models to delineate complex gene-gene interactions between folate, xenobiotic, TLR, and signal transducer and activator of transcription 4 (STAT4) signaling pathways in association with the molecular pathophysiology of SLE.
  
  
  METHODS
  We developed additive, multifactor dimensionality reduction (MDR), and artificial neural network (ANN) models.
  
  
  RESULTS
  The additive model, although the simplest, suggested a moderate predictability of 30 polymorphisms of these four pathways (area under the curve [AUC] 0.66). MDR analysis revealed significant gene-gene interactions among glutathione-S-transferase (GST)T1 and STAT4 (rs3821236 and rs7574865) polymorphisms, which account for moderate predictability of SLE. The MDR model for specific auto-antibodies revealed the importance of gene-gene interactions among cytochrome P450, family1, subfamily A, polypeptide 1 (CYP1A1) m1, catechol-O-methyltransferase (COMT) H108L, solute carrier family 19 (folate transporter), member 1 (SLC19A1) G80A, estrogen receptor 1 (ESR1), TLR5, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), thymidylate synthase (TYMS). and STAT4 polymorphisms. The ANN model for disease prediction showed reasonably good predictability of SLE risk with 30 polymorphisms (AUC 0.76). These polymorphisms contribute towards the production of SSB and anti-dsDNA antibodies to the extent of 48 and 40%, respectively, while their contribution for the production of antiRNP, SSA, and anti-cardiolipin antibodies varies between 20 and 30%.
  
  
  CONCLUSIONS
  The current study highlighted the importance of genetic polymorphisms in folate, xenobiotic, TLR, and STAT4 signaling pathways as moderate predictors of SLE risk and delineates the molecular pathophysiology associated with these single nucleotide polymorphisms (SNPs) by demonstrating their association with specific auto-antibody production.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad, 500082, India.
authors.forename: Yedluri
authors.initials: Y
authors.lastname: Rupasree
authors.affiliation: School of Chemical and Biotechnology, SASTRA University, Tirumalaisamudram, Thanjavur, 613401, India.
authors.forename: Shaik Mohammad
authors.initials: SM
authors.lastname: Naushad
authors.affiliation: School of Chemical and Biotechnology, SASTRA University, Tirumalaisamudram, Thanjavur, 613401, India.
authors.forename: Ravi
authors.initials: R
authors.lastname: Varshaa
authors.affiliation: School of Chemical and Biotechnology, SASTRA University, Tirumalaisamudram, Thanjavur, 613401, India.
authors.forename: Govindaraj Swathika
authors.initials: GS
authors.lastname: Mahalakshmi
authors.affiliation: Department of Rheumatology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, 500082, India.
authors.forename: Konda
authors.initials: K
authors.lastname: Kumaraswami
authors.affiliation: Department of Rheumatology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, 500082, India.
authors.forename: Liza
authors.initials: L
authors.lastname: Rajasekhar
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad, 500082, India. vijaykutala@gmail.com.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Kutala
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004843:Epistasis, Genetic; D047628:Estrogen Receptor alpha / Q000235:genetics; D005287:Ferredoxin-NADP Reductase / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000175:diagnosis / Q000235:genetics*; D015233:Models, Statistical; D016571:Neural Networks, Computer; D020641:Polymorphism, Single Nucleotide; D058978:Reduced Folate Carrier Protein / Q000235:genetics; D050797:STAT4 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction; D013940:Thymidylate Synthase / Q000235:genetics; D055815:Young Adult
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D007074:Immunoglobulin G; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; C000600377:TYMS protein, human; D013940:Thymidylate Synthase; D002394:Catechol O-Methyltransferase; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase