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
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