Tissue Antigens ISSN 0001-2815 BRIEF COMMUNICATION Genetic association of interferon-alpha subtypes 1, 2 and 5 in systemic lupus erythematosus N. Hirankarn 1 , M. Tangwattanachuleeporn 2 , J. Wongpiyabovorn 1 , J. Wongchinsri 3 & Y. Avihingsanon 4 1 Lupus Research Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand 2 Interdepartment of Medical Microbiology, Graduate School, Chulalongkorn University, Bangkok, Thailand 3 Department of Medicine, Nopparat Rajathanee Hospital, Bangkok, Thailand 4 Lupus Research Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Key words gene polymorphisms; interferon-alpha; systemic lupus erythematosus; Thai population Correspondence Nattiya Hirankarn, MD, PhD Lupus Research Unit Department of Microbiology Faculty of Medicine Chulalongkorn University Rama 4 Road Bangkok 10330 Thailand Tel: 166 2 256 4132 ext. 624 Fax: 166 2 252 5952 e-mail: fmednpt@md.chula.ac.th Received 10 March 2008; revised 14 June 2008, 25 July 2008; accepted 28 August 2008 doi: 10.1111/j.1399-0039.2008.01146.x Abstract In this study, the association between the systemic lupus erythematosus (SLE) susceptibility and the new candidate genes, IFNA1, IFNA2 and IFNA5 genes, major interferon-alpha subtypes, in responses to viral infection was investigated. Allele and genotype frequencies of each marker were compared between 150 SLE patients and 150 healthy control subjects. This study indicated that the A/A genotype of IFNA5 (22529) and the G/G genotype of IFNA1 (21823) were associated with the protection of SLE disease in a recessive model [P c ¼ 0.03, P ¼ 0.01, odds ratio (OR) ¼ 0.4, 95% confidence interval (CI) ¼ 0.2–0.8 and P c ¼ 0.09, P ¼ 0.03, OR ¼ 0.5, 95% CI ¼ 0.2–0.9, respectively). Multifactor dimensionality reduction analysis showed a marginal interaction between IFNA5 (22529) and IFNA1 (21823) gene, with a cross-validation consistency of 10 of 10 and a prediction error of 46% (permutation P-value ¼ 0.05). This is the first report of positive association of IFNA gene in SLE, especially the role of specific subtypes IFNA1 and IFNA5. There are several lines of evidence supporting the role of type I interferon (IFN) in systemic lupus erythematosus (SLE) disease. Gene expression profile in peripheral blood from SLE has identified the increased expression of type I IFN-related genes that reflect the dysregulation of type I IFN genes during the course of SLE (1–3). The observation that patients with malignancies or hepatitis C infection treated with IFN-alpha (IFNa) occasionally developed autoantibodies typical of those in SLE, and some presented with the clinical features of SLE help confirm that IFNa play a critical role in the pathogenesis of lupus (4–6). At the moment, it is not clear what the origin of this increased IFN type I is. Viral infections that lead to massive release of IFNa in vivo are not frequently detected in SLE patients prior to disease onset. Excitedly, recent genetic analysis focused on genes of type I IFN pathway shows IFN regulatory factor 5 (IRF5) gene as important SLE suscep- tibility gene in many populations (7–9). It is likely that many genetic alterations can lead to the sustained overproduction of IFNalpha/beta in human SLE. Other candidate genes are TYK2, although there is no report of replication yet (9). The 400-kb long type I IFN gene cluster on chromosome 9p21.3 is another interesting region because it has been linked with susceptibility to asthma and atopy (10) and lupus mouse model (11, 12). In SLE, there is evidence that susceptibility loci have been mapped to chromosome 9p24-21 with lod score of 2.08–2.27 (13). Type I IFN gene region consists of 15 functional IFN genes (13 IFNA genes, 1 IFNW gene and 1 IFNB gene). There were previous association studies in SLE using some markers within this region including IFNB1 (rs1424855, rs1424856 and rs1051922), IFNA6 (rs614541 and rs2383187), IFNA10 (rs10119910), IFNA17 (rs9298814) 588 ª 2008 The Authors Journal compilation ª 2008 Blackwell Munksgaard  Tissue Antigens 72, 588–592