Systemic Lupus Erythematosus (SLE) is a chronic, multiorgan autoimmune disease, predominantly affecting women, and resulting in significant morbidity and mortality. SLE is a multi-factorial disease whereby multiple genetic factors have been recognized to determine susceptibility. The long term goal of the investigators' studies is to identify genes involved in the etiopathogenesis of human SLE and characterize the mechanisms by which these genes influence disease development. The investigators state that this application is a natural extension of their ongoing work in the mouse models to human SLE. The hypothesis underlying this application is that the genes determining SLE phenotypes are prevalent in families of patients and can be identified using state-of-the-art molecular mapping and linkage analysis techniques. They propose the following: 1) to recruit and collect blood and DNA from 250 multi-case families with SLE; to classify all subjects for clinical and laboratory evidence of SLE, its organ involvement, severity of disease and its complications; this will be accomplished using four recruitment study sites, which are large lupus clinics; 2) conduct a genome wide search for SLE susceptibility loci, employing a multistage strategy beginning with a 20 cM map and using multipoint linkage analysis of affected relatives; efficiency of this search will be optimized by using a liberal significance criterion in the first phase, then revisiting regions identified using stringent significance criteria on multiple closely-spaced markers approximately 2.5 cM apart; 3) conduct multipoint linkage analysis of SLE in regions of the human genome sharing homologies with regions linked to mouse SLE. The studies in these regions of the human genome will use markers spacing and linkage criteria established for the final stage of the genome search. For all marker typing they will use automated fluorescence-based technologies. The investigators point out that this application integrates the talent of a multidisciplinary team, combining clinical expertise with highly qualified basic scientists with genetic, epidemiological, molecular biological and genetic analytic expertise. They further note that their institutional base represent a major and unique resource for the study of the genetics and epidemiology of SLE in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043815-03
Application #
6055617
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Serrate-Sztein, Susana
Project Start
1997-09-30
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Jacob, Chaim O; Eisenstein, Miriam; Dinauer, Mary C et al. (2012) Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase. Proc Natl Acad Sci U S A 109:E59-67
Chung, Sharon A; Taylor, Kimberly E; Graham, Robert R et al. (2011) Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. PLoS Genet 7:e1001323
Taylor, Kimberly E; Chung, Sharon A; Graham, Robert R et al. (2011) Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes. PLoS Genet 7:e1001311
International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN); Harley, John B; Alarcon-Riquelme, Marta E et al. (2008) Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 40:204-10
Pricop, L; Li, L; Salmon, J E et al. (2002) Characterization of the FcgammaRIIA promoter and 5'UTR sequences in patients with systemic lupus erythematosus. Genes Immun 3 Suppl 1:S47-50
Shai, R; Quismorio Jr, F P; Li, L et al. (1999) Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum Mol Genet 8:639-44