Association of genetic variations in the STAT4 and IRF7/KIAA1542 regions with systemic lupus erythematosus in a Northern Han Chinese population Ping Li a,† , Chunwei Cao b,c,† , Haixia Luan a,† , Chaohua Li b , Chaojun Hu a , Shulan Zhang a , Xiaofeng Zeng a , Fengchun Zhang a , Changqing Zeng b, *, Yongzhe Li a, * a Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China b Laboratory of Cancer Genomics, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100029, China c Graduate School of the Chinese Academy of Sciences, Beijing, China ARTICLE INFO Article history: Received 10 July 2010 Accepted 25 November 2010 Available online 15 December 2010 Keywords: Systemic lupus erythematosus Chinese Han Single-nucleotide polymorphisms STAT4 IRF7 KIAA1542 ABSTRACT Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. Genome-wide association studies have identified SLE susceptibility variations at the IRF7/KIAA1542 locus and with STAT4 gene in European populations. We decided to investigate the association of single-nucleotide polymorphisms (SNPs) in the IRF7/KIAA1542 region (rs4963128, rs2246614, and rs702966) and in STAT4 (rs7574865 and rs7582694) with SLE disease in a Northern Han Chinese population of 748 patients and 750 healthy controls. Our study indicated a strong association between rs7574865 (odds ratio = 0.68; 95% confidence interval 0.59 – 0.79; p = 1.57  10 -6 ) and SLE and between rs7574865 and the production of anti-Sm antibodies. Additionally, rs4963128 and rs2246614 were correlated with a variety of clinical subphenotypes, such as lupus nephritis, arthritis, and the production of anti-SSA/B autoantibodies, despite a lack of significant association between these two SNPs and SLE disease susceptibility in general.  2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. 1. Introduction Systemic lupus erythematosus (SLE) is a chronic, inflammatory autoimmune disease that can result in multiple organ damage and is characterized by production of autoantibodies to nuclear anti- gens and immune complex formation [1]. The etiology of SLE is not clearly understood, but genetic factors likely influence the patho- genesis, disease expression, and production of autoantibodies [2]. Population differences in disease prevalence and clinical manifes- tations exist [3]. The prevalence of SLE ranges from 31 to 70 cases per 100,000 persons among Chinese populations and from 7 to 71 cases per 100,000 persons in European populations [3,4]. Clinically, Asians have more renal involvement than Caucasians [5]. Studies in both mice and humans have demonstrated several genetic suscep- tibility loci that have roles in immune activation and regulation, as well as clearance of apoptotic cells. A major breakthrough in the understanding of pathogenesis of SLE was the discovery of the link between the interferon- (IFN-) activation pathway and SLE [6,7]. IFN- is part of the innate immune response, and abnormally high levels of IFN- have been observed in patients with SLE [8]. This state can promote dendritic cell maturation and proinflammatory cytokine production, which can affect stimulation of T-helper 1 pathways, promotion of B-cell activation, and regulation of apo- ptosis. Variants of certain IFN- pathway genes, including IRF5, IRF7, signal transducer and activator of transcription 4 (STAT4), and tyrosine kinase 2, have been associated with SLE suscepti- bility in multiple ethnic groups, but the complete impact of genetic variation on pathway activation is not fully understood [9 –11]. STAT4, the signal transducer and activator of transcription 4 gene, lies adjacent to STAT1 at 2q32.2–2q32.3, contains 24 ex- ons, and spans 122 kb. The STAT4 gene encodes a transcription factor that mediates the effect of several cytokines, including interleukin (IL)-12, the type I interferons, and IL-23 in T cells and monocytes. Thus, STAT4 has a role in T-helper type 1 and type 17 differentiation, monocyte activation, and IFN- production. In 2003, Jacob et al. [12] confirmed STAT4 deficiency was associ- ated with accelerated renal disease and increased mortality in a murine lupus model [13]. Associations between variants of the STAT4 single-nucleotide polymorphism (SNP) rs7574865 with other autoimmune diseases, such as rheumatoid arthritis [14,15], Sj×gren’s syndrome [16], inflammatory bowel disease, and type I diabetes mellitus [17], have been demonstrated. In addition to the link between STAT4 SNP rs7574865 and SLE, genome-wide association studies (GWAS) have demonstrated a link among rs3821236, rs7601754, and rs7582694 SNPs and SLE * Corresponding authors. E-mail addresses: czeng@big.ac.cn (C. Zeng) or yongzhelipumch@yahoo.com.cn (Y.Z. Li). † These authors contributed equally to this work. Human Immunology 72 (2011) 249 –255 Contents lists available at ScienceDirect 0198-8859/11/$32.00 - see front matter  2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.humimm.2010.12.011