Tumor necrosis factor-alpha single nucleotide polymorphisms in juvenile systemic lupus erythematosus Fatemeh Tahghighi a , Vahid Ziaee a,b , Mohammad Hassan Moradinejad b , Arezou Rezaei c , Sara Harsini c , Samaneh Soltani d , Maryam Sadr d , Maryam Mahmoudi e , Yahya Aghighi f , Nima Rezaei b,c,d,⇑ a Pediatric Rheumatology Research Group, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran b Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran c Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran d Molecular Immunology Research Center, Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran e School of Nutrition and Dietetics, Tehran University of Medical Sciences, Tehran, Iran f Department of Pediatrics, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran article info Article history: Received 17 November 2013 Revised 4 January 2014 Accepted 17 June 2015 Available online xxxx Keywords: Tumor necrosis factor-alpha Single-nucleotide polymorphism Juvenile systemic lupus erythematosus abstract Background: Juvenile systemic lupus erythematosus (JSLE) is a multi-system autoimmune disorder of unknown origin. Given the importance of the contribution of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-a), towards the pathogenesis of JSLE, this study was performed to assess TNFA gene polymorphisms in a case-control study. Methods: Fifty nine patients with JSLE were enrolled in this study as case group and compared with healthy control subjects. The frequency of alleles, genotypes, and haplotypes of TNFA single-nucleotide polymorphisms (SNPs) at positions À308 and À238 were evaluated, using polymerase chain reaction with sequence-specific primers method. Results: The G allele at position À238 in TNFA promoter region was significantly more frequent in patients with JSLE than in the healthy controls (P value < 0.001), while the frequency of A allele at the same position was significantly lower than controls. Furthermore, a significant positive association for G/G genotype at the same position was detected in patients’ group compared with control subjects (P value < 0.001). The GA haplotype of TNFA (positions À308, À238) was significantly less frequent in case group than in controls (P value < 0.001), while GG was the most frequent haplotype for TNFA in the patient group, compared to controls (P value < 0.01). Conclusions: Pro-inflammatory cytokine gene polymorphisms may influence susceptibility to JSLE. Particular TNFA gene variants are associated with JSLE and could be used as a genetic marker for suscep- tibility to JSLE. Ó 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. 1. Introduction Juvenile systemic lupus erythematosus (JSLE) is a multi-system autoimmune disorder of unknown origin with a remarkably diverse spectrum of immunologic and clinical abnormalities which appears before the age of 16 years [1–3]. JSLE is primarily charac- terized by exuberant production of autoantibodies as well as enhanced immune complex deposition, in company with autoreac- tive T cells, which together culminate in subsequent pathology in multiple target organs [4–6]. A complex interplay between genetic risk factors and environ- mental events seems to contribute towards disease initiation and progression [7,8]. Given the importance of the role of cytokines in the pathogen- esis of autoimmune and inflammatory diseases, deregulated cyto- kine production patterns have been reported as important actors in SLE [9]. Several circulating cytokine abnormalities result in impaired immune regulation and mediates tissue inflammation. Pro-inflammatory cytokines, like tumor necrosis factor-alpha (TNF-a), play a significant role in initiation and propagation of inflammatory and immune responses through enhancement of adhesion molecules expression, neutrophil activation, stimulation http://dx.doi.org/10.1016/j.humimm.2015.06.011 0198-8859/Ó 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. ⇑ Corresponding author at: Research Center for Immunodeficiencies, Children’s Medical Center Hospital, Dr Qarib St, Keshavarz Blvd, Tehran 14194, Iran. E-mail address: rezaei_nima@tums.ac.ir (N. Rezaei). Human Immunology xxx (2015) xxx–xxx Contents lists available at ScienceDirect www.ashi-hla.org journal homepage: www.elsevier.com/locate/humimm Please cite this article in press as: Tahghighi F et al. Tumor necrosis factor-alpha single nucleotide polymorphisms in juvenile systemic lupus erythemato- sus. Hum Immunol (2015), http://dx.doi.org/10.1016/j.humimm.2015.06.011