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 populations 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 replication study of candidate genetic variants identified in the GWAS, 3) localization of candidate risk alleles of novel effects associated with SLE in Asians, and 4) characterization 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 genetic etiology 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 for the development of new diagnostics and therapeutics to combat this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI083194-05
Application #
8514483
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$255,428
Indirect Cost
$39,313
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Kariuki, S N; Ghodke-Puranik, Y; Dorschner, J M et al. (2015) Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus. Genes Immun 16:15-23
Morris, D L; Fernando, M M A; Taylor, K E et al. (2014) MHC associations with clinical and autoantibody manifestations in European SLE. Genes Immun 15:210-7
Freedman, Barry I; Langefeld, Carl D; Andringa, Kelly K et al. (2014) End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol 66:390-6
Armstrong, D L; Zidovetzki, R; Alarcón-Riquelme, M E et al. (2014) GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region. Genes Immun 15:347-54
Dozmorov, Mikhail G; Wren, Jonathan D; Alarcon-Riquelme, Marta E (2014) Epigenomic elements enriched in the promoters of autoimmunity susceptibility genes. Epigenetics 9:276-85
Harley, John B; Zoller, Erin E (2014) Editorial: What caused all these troubles, anyway? Epstein-Barr virus in Sjögren's syndrome reevaluated. Arthritis Rheumatol 66:2328-30
Guthridge, Joel M; Lu, Rufei; Sun, Harry et al. (2014) Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription. Am J Hum Genet 94:586-98
Kottyan, Leah C; Davis, Benjamin P; Sherrill, Joseph D et al. (2014) Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease. Nat Genet 46:895-900
Lu-Fritts, Pai-Yue; Kottyan, Leah C; James, Judith A et al. (2014) Association of systemic lupus erythematosus with uranium exposure in a community living near a uranium-processing plant: a nested case-control study. Arthritis Rheumatol 66:3105-12
Kim-Howard, Xana; Sun, Celi; Molineros, Julio E et al. (2014) Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations. Hum Mol Genet 23:1656-68

Showing the most recent 10 out of 47 publications