doi: 10.1111/j.1744-313X.2008.00814.x © 2008 The Authors Journal compilation © 2008 Blackwell Publishing Ltd, International Journal of Immunogenetics 36, 15–19 15 Blackwell Publishing Ltd NRAMP1 (SLC11A1) gene polymorphisms that correlate with autoimmune versus infectious disease susceptibility in tuberculosis and rheumatoid arthritis Ö. Ates,* , ** L. Dalyan,* B. Müsellim,† G. Hatemi,‡ H. Türker,§ G. Öngen,† V. Hamuryudan‡ & A. Topal-Sarıkaya*¶ Summary NRAMP1 gene has multiple pleiotropic effects on macro- phage activation pathways. These pleiotropic effects may increase resistance to infections such as tuberculosis (TB), but may also lead to susceptibility of autoimmune diseases such as rheumatoid arthritis (RA). It has been hypothesized that allele 3 would be associated with autoimmune diseases, whereas allele 2 would be associated with infectious diseases, and genetic factors that enhanced survival in the epidemics of TB might have led to susceptibility for the development of RA. We analysed four NRAMP1 gene polymorphisms including 5′ promoter (GT) n (rs34448891), INT4 (469 + 14G/C) (rs3731865), 3′UTR (1729 + 55del4) (rs17235416) and D543N (codon 543, Asp to Asn) (rs17235409) in 112 patients with TB, 98 patients with RA, 80 healthy controls for TB and 122 healthy controls for RA using ARMS-PCR and PCR-RFLP. We found a significant association between INT4 and RA (P = 0.004, odds ratio: 2.06, 95% CI: 1.24 – 3.41), but no significant differences between 5′ promoter, D543N, 3′UTR polymorphisms and RA. There were no associations between NRAMP1 gene polymorphisms and TB. Similarly, no significant differences were observed between NRAMP1 polymorphisms and rheumatoid factor positivity and erosive disease in RA and localization of TB. INT4 polymorphism may be associated with RA in Turkish patients. Introduction Natural resistance associated macrophage protein 1 (NRAMP1) gene, also named as solute carrier family 11 member a1 gene (SLC11A1), was originally described for its role in the regulation of resistance and susceptibility to a range of intramacrophage pathogens in mice. NRAMP1 has multiple pleiotropic effects on macrophage activation pathways, such as up-regulation of the CXC chemokine KC, tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), inducible nitric oxide syntase (iNOS) and major histocompatibility complex (MHC) class II expression as well as tumouricidal and antimicrobial activity (Blackwell & Searle, 1999). A link between NRAMP1 and susceptibility to auto- immune and infectious diseases has been the subject of several previous reports (Shaw et al., 1996; Hofmeister et al., 1997; Abel et al., 1998; Bellamy et al., 1998; Maliarik et al., 2000; Sanjeevi et al., 2000; Nishino et al., 2005; Yen et al., 2006). We had also found an association between NRAMP1 and progressive systemic sclerosis (Ates et al., 2008). It was suggested that the epidemiology of rheumatoid arthritis (RA) resembles the epidemiology of deaths due to tuberculosis (TB), two centuries ago, according to this hypothesis, genetic factors that enhanced survival in the epidemics of TB might have led to susceptibility for the development of RA (Mobley, 2004). It has been postulated that high expression level of NRAMP1 associated with allele 3 in 5′ promoter (GT) n microsatellite is functionally linked to autoimmune disease susceptibility, whereas the low expression level of NRAMP1 associated with allele 2 is linked to infectious disease susceptibility. In other words, allele 3 protects against infectious disease and allele 2 protects against autoimmune disease (Searle & Blackwell, 1999). To test this plausible association, we analysed NRAMP1 5′ promoter (GT) n (rs34448891) polymorphism. In addition, we also analysed NRAMP1 INT4 (469 + 14G/C) (rs3731865), D543N (codon 543, Asp to Asn) (rs17235409) and 3′UTR (1729 + 55del4) (rs17235416) polymorphisms in Turkish patients with TB and RA. INT 4 contains exon 4a which introduce a termination codon in exon V (Cellier et al ., 1994). Any variant that causes elimination of the splice acceptor site for transcription may influence the amount of functional * Department of Molecular Biology and Genetics, Science Faculty, † Chest Disease Department, Cerrahpasa Medical Faculty, ‡ Rheumatology Department, Cerrahpasa Medical Faculty, Istanbul University, § Chest Disease Department, Sureyyapasa Chest Diseases and Thoracic Surgery Education and Research Hospital, and ¶ Research and Application Center for Biotechnology and Genetic Engineering, Istanbul University, Istanbul, and ** Department of Medical Biology, Medical Faculty, Gaziosmanpasa University, Tokat, Turkey Received 7 May 2008; revised 7 May 2008; accepted 9 October 2008 Correspondence: Ömer Ates, Department of Molecular Biology and Genetics, Science Faculty, Istanbul University, 34118 Vezneciler, Istanbul, Turkey. Tel: +90 21 2455 5700 ext. 15139; Fax: +90 21 2455 5811; E-mail: omerates27@yahoo.com