Contents lists available at ScienceDirect Cytokine journal homepage: www.elsevier.com/locate/cytokine Cytokine genes multi-locus analysis reveals synergistic influence on genetic susceptibility in Indian SLE – A multifactor-dimensionality reduction approach Vinod Umare a , Vandana Pradhan a , Sneha Dadheech b , Anjali Rajadhyaksha c , Kanjaksha Ghosh a , Anita Nadkarni a, ⁎ a National Institute of Immunohaematology, Indian Council of Medical Research, Mumbai, Maharashtra 400012, India b Hemoglobinopathies Satellite Centre, National Institute of Immunohaematology (ICMR), Chandrapur, Maharashtra 442401, India c Department of Medicine, King Edward Memorial Hospital, Parel, Mumbai, Maharashtra 400012, India ARTICLE INFO Keywords: Gene-gene interaction MDR Cytokines Indian SLE Autoimmune diseases ABSTRACT Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with unclear etiology. Several loci as- sociated with genetic susceptibility for lupus have been described. However, it lacks reports on cytokine gene- gene interactions among SLE patients from Asian population. Epistasis interaction among single nucleotide polymorphisms (SNPs) of cytokine genes in Indian SLE patients was tested using multifactor-dimensionality reduction (MDR) analysis. A total of fourteen SNPs lacking linkage disequilibrium among different cytokines genes were genotyped in a cohort of 200 SLE patients and 201 healthy individuals as controls of Indian origin. A high degree of synergism among Lymphotoxin-α (LT-α), Interleukin-1β (IL-1β) and Interleukin-10 (IL-10) gene polymorphisms was detected in our SLE patients. Furthermore, by virtue of biological inter-relations among different cytokines, a high strength of interactions was observed among pro-inflammatory (IL-1β, IL-6) and anti- inflammatory (IL-10) cytokine gene SNPs. Also, among studied pro-inflammatory cytokines and chemokines, a strong synergistic effect among Tumor Necrosis Factor-α (TNF-α), LT-α and Monocyte Chemo-attractant Protein- 1 (MCP-1) SNPs was occurred. A nature of strong interaction among the candidate cytokine genes may speculate a proactive role in causing genetic susceptibility to the disease in SLE patients with Indian origin. 1. Introduction Systemic lupus eryhtematosus (SLE) is a prototype autoimmune disorder characterized by production of auto-antibodies to nuclear an- tigens, deposition of immune complexes and ultimately damage to multiple organs. Though the etiology of the disease is not clearly un- derstood, environmental and genetic factors are known to elicit the susceptibility to SLE [1,2]. Although the discovery and validation of multiple loci including HLA-DRB1 and DQB1 for SLE [3], it is necessary to look for synergistic effect on the genetic susceptibility caused due to combined heritability of different loci. To deal with this problem, gene- gene interaction analysis would play a vital role. Multifactor Dimensionality Reduction (MDR) is a computer tool specifically intended for detecting and assessing epistasis interactions among different genes so that outcomes can decipher the cumulative role of various genes helpful in predicting the susceptibility and severity of disease [4,5]. MDR, a non-parametric tool was designed to search for gene-gene as well as gene-environment interactions by identifying a multi-locus model for association with disease [6,7]. Prime objective of MDR is to alter the representation of data using a constructive induction algorithm. Each genotypes combination is labeled as high risk-low risk using dichotomous disease status i.e. cases-controls [5]. MDR has greater power than logistic-regression analysis for testing interaction among correlated predictors [8]. Thus, the aim of this study was to analyze potential influence of single nucleotide polymorphisms (SNPs) in cytokine genes on genetic susceptibility to the disease using MDR analysis in Indian SLE patients. 2. Materials and methods 2.1. Study population Two hundred patients (184 females and 16 males) fulfilling the American College of Rheumatology (ACR) 1997 revised classification https://doi.org/10.1016/j.cyto.2020.155240 Received 22 December 2019; Received in revised form 21 April 2020; Accepted 4 August 2020 ⁎ Corresponding author at: ICMR-National Institute of Immunohaematology, 13th Floor, NMS Bldg., King Edward Memorial Hospital, Parel, Mumbai 400012, India. E-mail address: anitahnadkarni@yahoo.com (A. Nadkarni). Cytokine 135 (2020) 155240 1043-4666/ © 2020 Published by Elsevier Ltd. T