Immunology Letters 228 (2020) 70–75 Available online 7 October 2020 0165-2478/© 2020 Published by Elsevier B.V. on behalf of European Federation of Immunological Societies. IL-18 variant increases risk of enhanced HBV DNA replication in chronic hepatitis Walid Ben Selma a, b, c, *, Sana Alibi b , Mohamed Ali Smach b , Afef Saad d , Jalel Boukadida a, b, d a Laboratory of Microbiology, UR12SP34, University Hospital Farhat Hached, Sousse, Tunisia b Laboratory of Biological and Genetic Markers Studying for Early Diagnosis and Follow-Up of Neurological Diseases, LR18ES47, Faculty of Medicine, Sousse, Tunisia c Higher Institute of Applied Sciences and Technology, Mahdia, Tunisia d Department of Microbiology, Faculty of Medicine, Sousse, Tunisia A R T I C L E INFO Keywords: Chronic HBV infection DNA replication Interleukin-18 Polymorphism Susceptibility ABSTRACT Background: The outcome ofhepatitis B (HBV) infection is infuenced by immune responses and host genetics. Interleukin-18 (IL-18) is a determinant factor in controlling the balance of Th1/Th2 during antiviral response. Weexamine therole of two functional polymorphisms -607A/C and-137A/C inIL-18 gene with risk of chronic HBV infection. Methods and Results: Genomic DNA isolates were obtained from 200 seropositive cases stratifed according to their HBV DNA loads, and 200 blood donorsas a control population. Genotypes of the two polymorphisms were identifed by ARMS-PCR method. The -607A allele, the-607AA and -607AC genotypes were associated with increased risk to develop chronic HBV infection (1.98, 5.11 and 3.5-fold risks, respectively). By contrast, the -137C minor allele and CG genotype had protected effects against chronic HBV infection. We found that -607A allele, -607AA and -607AC genotypes were signifcantly more frequent in patient’s group with high HBV DNA levels compared to patient group with low HBV DNA level. Additionally, they were asso- ciated with increased 1.72, 6.04 and 3.28-fold risk of high HBV DNA replication. Patients carrying “-607A/-137 C” or “-607A/137 G” haplotypes presented a high risk to develop chronic HBV infection (OR = 3.27; OR = 4.32, respectively). Conclusions: Taken together, our data suggest that theIL-18 -607A/C functional polymorphism was associated with susceptibility to enhanced replicative form of HBV DNA in chronic infection. 1. Introduction It is estimated that worldwide over two billion people have been exposed to the hepatitis B virus (HBV), of whom 350–400 million are chronically infected, and annually causes 887 000 deaths from compli- cations [1,2].The spectrum of disease and natural history of chronic HBV infection are diverse, ranging from the inactive carrying state to the progressive chronic hepatitis B (CHB), which progress into cirrhosis or hepatocellular carcinoma [3].There is cumulative evidence that indi- vidual genetic differences especially those regulating the immune response play a fundamental role in determining the outcome of HBV infection: hepatic infammatory aggravation, progression to fbrosis or cirrhosis, increased risk of developing hepatocellular carcinoma, or a negative therapy response [4–8].Thus, several investigators have focused their interest on the role of single nucleotide polymorphisms present in cytokines as we have recently reported [5], chemokines, or their receptors implicated in HBV pathogenesis [6,7,9,10]. Previous studies have shown that interleukin-18 (IL-18) is an important proinfammatory cytokine, playing a determinant role in viral clearance and protective immunity against viral infections [11,12] by inducing IFN-γ synthesis [13]. Through acting synergistically with IL-12, IL-18 improves both the cytotoxicity of natural killer (NK) cells andan effective T helper 1 (Th1) response against viral infections [14]. IL-18 gene with its six exons and fve introns is positioned on chro- mosome 11q22.2-q22.3 [15]. Out of the known single nucleotide poly- morphisms (SNPs) of IL-18 gene, -137 (rs187238) and -607 (rs1946518), situated in the promoter’s genomic sequence have been shown to alter the expression of IL-18 gene [8,16]. The minor alleles -607A and -137C * Corresponding author at: Laboratory of biological and genetic markers studying for early diagnosis and follow-up of neurological diseases, LR18ES47, Faculty of medicine – Av. Ibn elJazzar-4000, Sousse, Tunisia. E-mail address: walid.bensalma@issatmh.u-monastir.tn (W. Ben Selma). Contents lists available at ScienceDirect Immunology Letters journal homepage: www.elsevier.com/locate/immlet https://doi.org/10.1016/j.imlet.2020.10.002 Received 15 July 2020; Received in revised form 24 September 2020; Accepted 1 October 2020