title: Polymorphisms in the promoter region of iNOS predispose to rheumatoid arthritis in south Indian Tamils.
abstract: Nitric oxide synthase (NOS) catalyses the production of nitric oxide (NO) from L-Arginine, which participates in diverse biological processes including inflammation and apoptosis. Macrophages, chondrocytes, osteoblasts and osteoclasts express inducible NOS (iNOS) at the site of synovial inflammation. NO produced at the inflamed joint may contribute to peri-articular bone loss, mediate apoptosis and regulate Th1/Th2 balance in rheumatoid arthritis (RA). Variations in the promoter region of NOS gene regulate the nitric oxide synthase expression and iNOS (NOS2) polymorphisms have been associated with susceptibility to autoimmune disorders. Hence, this study was conducted to identify the possible contributions of NOS2 -1659G/A, -1026C/A, -277A/G promoter polymorphisms towards development of RA in South Indian Tamils. A total of 242 (219 females, 23 males) patients with RA (mean age 41.2 ± 10.9 years, disease duration 8.5 ± 4.3 years) and 279 age- and sex-matched healthy individuals of South Indian Tamil ethnicity were genotyped for NOS2 -1659C/T, -1026G/T and -277A/G promoter polymorphisms by TaqMan chemistry. Nature of disease (erosive or nonerosive), the presence of extra-articular manifestations, seropositivity for rheumatoid factor and anticyclic citrullinated peptide, serum C-reactive protein (CRP) level and response to therapy were assessed for all patients. The three single nucleotide polymorphisms (SNPs) were in Hardy-Weinberg equilibrium. The frequency of GG genotype and G allele of NOS2-277 was higher in patients (pc = 5.7 × 10-9, OR = 6.09, 95% CI = 3.09-12.8 and pc = 4 × 10-13, OR = 2.37, 95% CI = 2.06-3.62, respectively) compared to controls. Similarly, the frequency of NOS2-1026 (rs2779249) GT genotype and the T allele was higher in patients with RA (pc = .01, OR = 1.61, 95% CI = 1.09-2.36, and pc = .04, OR = 1.40, 95% CI = 1.02-1.91, respectively). However, no significant difference in frequency of NOS2-1659C/T polymorphism was observed between patients and controls. None of the studied SNPs were associated with erosive disease, seropositivity or extra-articular manifestations. The -277A/G and -1026 G/T promoter polymorphisms in iNOS may confer susceptibility to RA in South Indian Tamils.
authors.affiliation: Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.
authors.forename: V S
authors.initials: VS
authors.lastname: Negi
authors.affiliation: Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.|INSERM, UMRS, U1160, Saint Louis Hospital, Paris, France.
authors.forename: C M
authors.initials: CM
authors.lastname: Mariaselvam
authors.affiliation: Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.
authors.forename: D P
authors.initials: DP
authors.lastname: Misra
authors.affiliation: Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.
authors.forename: N
authors.initials: N
authors.lastname: Muralidharan
authors.affiliation: Jean Dausset laboratory of Immunology and Immunogenetics and LabExTransplantex, Saint Louis Hospital, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Fortier
authors.affiliation: INSERM, UMRS, U1160, Saint Louis Hospital, Paris, France.|Jean Dausset laboratory of Immunology and Immunogenetics and LabExTransplantex, Saint Louis Hospital, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Charron
authors.affiliation: INSERM, UMRS, U1160, Saint Louis Hospital, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Krishnamoorthy
authors.affiliation: INSERM, UMRS, U1160, Saint Louis Hospital, Paris, France.|Jean Dausset laboratory of Immunology and Immunogenetics and LabExTransplantex, Saint Louis Hospital, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Tamouza
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002097:C-Reactive Protein; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007194:India; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: D009569:Nitric Oxide; D002097:C-Reactive Protein; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II
keywords: CRP; NOS2 promoter polymorphism; Rheumatoid arthritis; South India; Susceptibility; iNOS