Our genome wide association study (GWAS) in systemic lupus erythematosus (SLE) cases and controls of European-derived ancestry (EA) has identified 14 new genetic effects that influence risk to SLE. Importantly, SLE is more frequent in African-Americans, Hispanics (admixed Amerindians), and Asians than it is in individuals of EA. The strongest EA associations for SLE are within the HLA region but its role in other ethnicities is not well defined.
The aims of this collaborative POI are to complete 1) intensive studies of the HLA associations in N>10,G00 EA individuals and more than 6,000 individuals ofAfrican-American, Hispanic (admixed Amerindians), and Asian descent, 2) separate and comparative GWAS in African-Americans, Hispanics (admixed Amerindians), and Asians, and 3) fine map and confirm associations in an additional 6,000 individuals from the three non-EA populations. The studies are highly integrated and interdependent. The resulting dataset will contain over 100 billion genetic markers, various types of genetic variation and multiple phenotypic and clinical variables. Thus, the Data Analysis and Bioinformatics Core at Wake Forest University Health Sciences will provide expertise and personnel for study design, data storage and manipulation, analysis, novel methods applications and development,filtering,interpretation, summarization and manuscript preparation. The Core will be responsible for data dissemination both within the POI and requesting investigators outside the POI and deposition into dbGaP. Knowing the genetic etiology of lupus will provide the basis to develop a deep understanding of causation and pathophysiology that will lead to new diagnostics, preventive measures and therapeutics that should transform the practical management of SLE.

Public Health Relevance

Systemic lupus erythematosus is a life-threatening inflammatory autoimmune disease of tremendous personal and public health burden. A complete understanding of this disease is not possible without the kind of comprehensive multiethnic exploration of the human genome such as that proposed in this program project.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI083194-05
Application #
8514485
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
$245,317
Indirect Cost
$37,756
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Patel, Zubin; Lu, Xiaoming; Miller, Daniel et al. (2018) A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. Hum Mol Genet :
Hanscombe, Ken B; Morris, David L; Noble, Janelle A et al. (2018) Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans. Hum Mol Genet 27:3813-3824
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
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
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
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
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
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
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

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