Lupus (2019) 0, 1–10 journals.sagepub.com/home/lup PAPER Impact of functional IL-18 polymorphisms on genetic predisposition and diverse clinical manifestations of the disease in Indian SLE patients V Umare 1 , V Pradhan 1 , S Nath 2 , A Rajadhyaksha 3 , K Ghosh 1 and AH Nadkarni 1 1 National Institute of Immunohaematology, Indian Council of Medical Research, Mumbai, India; 2 Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, United States of America; and 3 Department of Rheumatology, King Edward Memorial Hospital, Mumbai, India Several studies have demonstrated associations between interleukin-18 polymorphisms and risk of systemic lupus erythematosus in different populations except one of Indian origin. We therefore investigated for the influence of interleukin-18 (-1297T/C, -607A/C, -137G/ C; þ 105A/C) polymorphisms on genetic susceptibility and clinical expression of the disease in Indian systemic lupus erythematosus patients. A total of 200 systemic lupus erythematosus patients and 201 controls were recruited. Genotyping of interleukin-18 polymorphisms were performed by polymerase chain reaction-restriction fragment length polymorphism. Serum interleukin-18 levels were measured by enzyme-linked immunosorbent assay. Interleukin-18 (-1297T/C; -137G/C) polymorphisms showed significant association with genetic susceptibility to the disease in our systemic lupus erythematosus cohort. Stratification analysis revealed -1297CC and -1297C associated with renal involvement (odds ratio ¼ 3.4, correcting p value ¼ 0.0207), (odds ratio ¼ 2.0, correcting p value ¼ 0.0054) respectively. Additionally, -1297C allele frequency was significantly increased in patients with anti-nucleosome antibody (odds ratio ¼ 2.1, correcting p value ¼ 0.0301). Haplotype analysis showed CC haplotype strongly associated with serositis (odds ratio ¼ 9.1, correcting p values ¼ 0.0009) and neuro- logic involvement (odds ratio ¼ 9.3, correcting p value ¼ 0.0018). We reported a 2.7-fold increase in serum interleukin-18 levels in patients (511.5  242.3 pg/ml) compared to controls (189.4  80.8 pg/ml) (p < 0.0001). Furthermore, interleukin-18 levels were positively correlated with disease activity (r ¼ 0.548, p ¼ 0.0001) and renal involvement in the patients with lupus nephritis (r ¼ 0.569, p < 0.0001). In summary, interleukin-18 polymorphisms elucidated in this study appear to confer genetic susceptibility to the disease and are associated with renal, serositis and neurologic involvement in Indian systemic lupus erythematosus patients. Lupus (2019) 0, 1–10. Key words: Interleukin-18 polymorphisms; Indian systemic lupus erythematosus; pro-inflammatory cytokines Introduction Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by the produc- tion of autoantibodies. The disease course is viewed by unpredictable flares and remissions. Diverse clinical manifestations are observed, including rash and disfiguring of skin, renal failure, hemolytic anemia and arterial or venous thrombosis. 1 Interleukin-18 (IL-18) is a pleotropic pro-inflam- matory cytokine encoded by the IL-18 gene. Single nucleotide polymorphisms (SNPs) in the IL-18 gene have been reported to be associated with SLE susceptibility and may contribute to dis- ease pathogenesis. 2,3 IL-18 is a member of the IL-1 superfamily whose cleavage and maturation resembles that of IL-1b, another member of the family. IL-18 is expressed by numerous immune cells and is known to be involved in multiple biological functions. IL-18, in combination with IL-12, induces IFN-g production Correspondence to: Anita H. Nadkarni, National Institute of Immunohaematology, 13th Floor, NMS Building, King Edward Memorial Hospital, Parel, Mumbai-400012, India. Email: anitahnadkarni@yahoo.com Received 31 August 2018; accepted 7 February 2019 ! The Author(s), 2019. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/0961203319834677