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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI083194-04
Application #
8380584
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$277,241
Indirect Cost
$32,303
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Sun, Celi; Molineros, Julio E; Looger, Loren L et al. (2016) High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat Genet 48:323-30
Alarcón-Riquelme, Marta E; Ziegler, Julie T; Molineros, Julio et al. (2016) Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture. Arthritis Rheumatol 68:932-43
Deng, Yun; Zhao, Jian; Sakurai, Daisuke et al. (2016) Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production. Ann Rheum Dis 75:2007-2013
Lessard, Christopher J; Sajuthi, Satria; Zhao, Jian et al. (2016) Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans. Arthritis Rheumatol 68:1197-1209
Munroe, Melissa E; Lu, Rufei; Zhao, Yan D et al. (2016) Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification. Ann Rheum Dis 75:2014-2021
Zhao, Jian; Giles, Brendan M; Taylor, Rhonda L et al. (2016) Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA. Ann Rheum Dis 75:242-52
Taylor, Rhonda L; Cruickshank, Mark N; Karimi, Mahdad et al. (2016) Focused transcription from the human CR2/CD21 core promoter is regulated by synergistic activity of TATA and Initiator elements in mature B cells. Cell Mol Immunol 13:119-31
Liu, Ke; Kurien, Biji T; Zimmerman, Sarah L et al. (2016) X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome. Arthritis Rheumatol 68:1290-1300
Zhao, Jian; Wu, Hui; Langefeld, Carl D et al. (2015) Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus. Clin Immunol 161:157-62
Martins, M; Williams, A H; Comeau, M et al. (2015) Genetic association of CD247 (CD3?) with SLE in a large-scale multiethnic study. Genes Immun 16:142-50

Showing the most recent 10 out of 78 publications