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
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
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
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
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
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 68:1197-209
Lu, Rufei; Munroe, Melissa E; Guthridge, Joel M et al. (2016) Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies. J Autoimmun 74:182-193
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
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 68:1290-300
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
Lu, Xiaoming; Zoller, Erin E; Weirauch, Matthew T et al. (2015) Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression. Am J Hum Genet 96:731-9

Showing the most recent 10 out of 80 publications