Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim Relapsing-remitting multiple sclerosis: A profile of interleukine-1 gene cluster polymorphisms in Iraqi patients Milad A.S. Al-Naseri a , Ehab D. Salman b , Ali H. Ad'hiah c, ⁎ a Iraqi Ministry of Health, Baghdad, Iraq b Biotechnology Department, College of Science, University of Baghdad, Baghdad, Iraq c Tropical-Biological Research Unit, College of Science, University of Baghdad, Baghdad, Iraq ARTICLE INFO Keywords: Relapsing-remitting multiple sclerosis Intrleukin-1 Single nucleotide polymorphisms Haplotype Logistic regression analysis ABSTRACT In this case-control study, 68 relapsing-remitting multiple sclerosis (RRMS) patients and 133 control were genotyped for IL1A -889 (rs1800587), IL1B -511 (rs16944), IL1B +3962 (rs1143634), IL1R1 pst11970 (rs2234650) and IL1RN mspa1 11,100 (rs315952) variants. Sequence-specific-primer-polymerase-chain-reaction was the geno- typing method. Logistic regression analysis demonstrated protective effects of IL1B -511 , IL1R1 pst11970 and IL1RN mspa1 11,100 against MS incidence, while no association was found with IL1A -889 and IL1B +3962 variants. Allele frequencies showed no significant gender, medication or expanded disability status scale-associated variation. Haplotype analysis suggested 4.31-fold increased odds for MS in subjects with C-T-C-C-T haplotype of the respective loci. In conclusion, IL-1 gene variants influence MS susceptibility in Iraqi population. 1. Introduction Multiple sclerosis (MS) is inflammatory autoimmune disease char- acterized by multiple focal demyelinated plaque formations in white matter of the central nervous system (CNs) (Lassmann et al., 2007). Although, the exact etiology of MS is not well-defined, multiple inter- actions between host genetic susceptibility and environmental factors are required to initiate the pathogenic episodes, in which immune components are consequently involved (Comabella and Khoury, 2012). The autoimmune inflammatory response in MS is initiated by auto- reactive T lymphocytes that mount exaggerated immune responses against autoantigens of the CNS and promote inflammation, demyeli- nation, gliosis and neuroaxonal degeneration (Dendrou et al., 2015). However, it has been demonstrated that lymphocyte migration across the blood–brain barrier is regulated by activation of proinflammatory cytokines, which showed upregulated levels in cerebrospinal fluid (CSF) and sera of MS patients (Khaibullin et al., 2017). A panel of proinflammatory and anti-inflammatory cytokines are suggested to be key immunological components in the onset, develop- ment, progression and severity of MS; including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-1, IL-3, IL-4, IL-6, IL-10, IL-12, and IL- 18 (Wang et al., 2018). IL-1 is presented by super-family of im- munomodulatory cytokines and natural antagonists that have pleio- tropic effects and exert a prominent role in pathogenesis of several auto-inflammatory conditions including MS (McEntee et al., 2019). IL- 1α and IL-1β, key members of IL-1 family, are proinflammatory med- iators and their pathophysiological impact on the CNS and progression of chronic neurodegenerative diseases has been suggested (Shaftel et al., 2008). Further, neuroinflammation has been marked with upre- gulated expression of IL-1α and IL-1β in the CNS together with acti- vation of microglial cells (Liu and Quan, 2018). In MS, high levels of both cytokines have been found in white matter lesions, and accord- ingly, the impact of IL-1α and IL-1β on immunopathology of MS has been augmented (Lin and Edelson, 2017; Musella et al., 2020). Inter- leukin-1 receptor antagonist (IL1-RA) is the naturally occurring an- tagonist of IL-1α/IL-1β signaling pathways. It competitively inhibits both cytokines by binding the IL-1 receptor type I (IL-1R1) (Dinarello, 2018). IL1α, IL1β, IL-1R1 and IL1RA are encoded by genes mapped to the long arm of chromosome 2 at region 2q13–14 (IL1A, IL1B, IL1R1 and IL1RN, respectively) (Yazdi and Ghoreschi, 2016). These genes are re- cognized to harbor extensive single nucleotide polymorphisms (SNPs) that are reported to influence susceptibility to autoimmune diseases, as well as impact gene expression of the respective loci (Khazim et al., 2018). With respect to MS, a considerable attention has been directed to determine the role of IL-1 gene family SNPs in predisposition to disease. Although, some findings are inconsistent, these SNPs have been sug- gested to influence clinical course and risk of MS in different ethnic populations (Aggelakis et al., 2010; Asgharzadeh et al., 2020; Borzani et al., 2010; Dinčić et al., 2006; Heidary et al., 2014; Hooper-Van Veen https://doi.org/10.1016/j.jneuroim.2020.577291 Received 5 April 2020; Received in revised form 11 June 2020; Accepted 12 June 2020 ⁎ Corresponding author at: Tropical-Biological Research Unit, College of Science, University of Baghdad, Al-Jadriya, Baghdad, Iraq. E-mail address: dr.ahadhiah@sc.uobaghdad.edu.iq (A.H. Ad'hiah). Journal of Neuroimmunology 346 (2020) 577291 0165-5728/ © 2020 Elsevier B.V. All rights reserved. T