SLEGEN, a productive multi-institutional consortium of lupus investigators, has successfully conducted a genome wide association study (GWAS) with independent replication in European-derived populations and has both confirmed previous candidate genes and discovered multiple new genetic effects. As a result of SLEGEN, and the work of others, the genetic variants known to contribute to the risk of lupus now include ITGAM (CD11b, CR3), STAT4, BANK1, BLK, HLA-DR, IRF5, FCGR3A, FCGR2A, 01 q. Complement 04, and PTPN22. However, both the phenotypic variation in other populations with different ancestries and initial data indicate that not all European variants have similar roles in these populations, which strongly suggests that we have much to learn about the genetic architecture of human lupus. To our knowledge, GWAS of SLE in Asian populafions have not been published. Most Asian SLE- associated genetic variants reported to date test candidate genes using modest sample collections and many such genetic effects fail to be replicated. A collaborative network of SLEGEN groups and international lupus investigators will have >6,000 cases and controls of Asian origin available for 1) performing a GWAS using ~1.8 million markers, 2) a large replicafion study of candidate genefic variants identified in the GWAS, 3) localization of candidate risk alleles of novel effects associated with SLE in Asians, and 4) characterizafion of functional consequences of associated alleles/haplotypes. This project will complement similar multistage GWAS approaches in African-Americans (Project 2) and Amerindian admixed Hispanics (Project 3) as well as the MHO fine mapping studies (Project 1), all of which will provide a unique opportunity for trans-racial mapping that will identify variants that are either shared across or unique within multiple racial groups. We will focus on the identification of novel Asian specific risk variants for SLE and will characterize how these gene variants may predispose to SLE in Asians. The resulting level of understanding promises to establish the genefic efiology of lupus, and spawn new diagnostics, prognostics, and therapeutics, providing benefits to this and many related illnesses.

Public Health Relevance

; Our goals of this study are to identify novel loci that predispose to SLE primarily in Asians, and to understand how these genetic variants increase the risk for SLE. Results from these studies will increase our understanding of the disease pathogenesis, and will lay the foundation forthe development of new diagnostics and therapeutics to combat this disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-KS-I)
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Oklahoma Medical Research Foundation
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