Systemic lupus erythematosus (SLE or lupus) is a complex, multi-organ, clinically heterogeneous, potentially fatal autoimmune disease with substantial genetic and environmental components. In U.S., SLE affects ~2 million people, mostly women (~90%), and prevalence is >3-5 times higher in individuals of African, Asian and Hispanic ancestries compared to European ancestry. Despite its public health importance, SLE pathogenesis is not well understood. Infection is a leading cause of morbidity and mortality, accounting for >25% of deaths in SLE patients. Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide are key for defense against invading microbial pathogens, and are produced by the multi-protein NADPH- oxidase (NADPHO) system during phagocytosis. This multi-protein complex is encoded by 7 essential genes: NCF1, NCF2, NCF4, CYBA,CYBB, Rac1 or Rac2. Although NADPHO is likely to be important in SLE pathophysiology, thus far, none of the 7 genome-wide association studies detected SLE association. Using large multi-ethnic cohorts (N >17,000 from European-Americans (EA), African-Americans (AA), Hispanics (HS), and Koreans (KR)), we have identified at least 7 independent and potentially functional SLE-susceptibility variants (10-44

Public Health Relevance

Lupus is a significant global health problem. In the United States alone, more than 2,000,000 individuals suffer from this devastating disease, especially people of African, Asian, or Hispanic ancestry where prevalence is 3 to 5 times higher than in those of Caucasian ancestry. Our study will identify potentially functional variants within genes of the NADPH oxidase system and their relative contributions to the development of lupus, as well as their contributions in a clinical subset of patients of each ethnicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI103399-02
Application #
8651414
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Johnson, David R
Project Start
2013-04-15
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
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
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
Zhou, Xu-Jie; Nath, Swapan K; Qi, Yuan-Yuan et al. (2014) Brief Report: identification of MTMR3 as a novel susceptibility gene for lupus nephritis in northern Han Chinese by shared-gene analysis with IgA nephropathy. Arthritis Rheumatol 66:2842-8
Maiti, Amit K; Kim-Howard, Xana; Motghare, Prasenjeet et al. (2014) Combined protein- and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM. Hum Mol Genet 23:4161-76
Shah, Dilip; Mahajan, Nidhi; Sah, Sangita et al. (2014) Oxidative stress and its biomarkers in systemic lupus erythematosus. J Biomed Sci 21:23
Namjou, Bahram; Kim-Howard, Xana; Sun, Celi et al. (2013) PTPN22 association in systemic lupus erythematosus (SLE) with respect to individual ancestry and clinical sub-phenotypes. PLoS One 8:e69404