The possibility that different autoimmune phenotypes might share particular genetic linkages has been bolstered by a meta-analysis of the available data (Becker, et al, PNAS 95:9979-9984, 1998). In addition, our collection of pedigrees multiplex for systemic lupus erythematosus (SLE), as a clinical disease, contain many members who do not have lupus, but who do have autoimmune findings. Examples include lupus-related positive serology and other disorders thought to be autoimmune in origin such as myasthenia gravis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, psoriasis, and diabetes. Recently, we published the results of a genome scan using clinical lupus as a phenotype (Moser, et al. PNAS 95:14869-14874, 1998). In 94 pedigrees studied, there are 223 confirmed SLE affecteds and 594 family members, 17 percent of who report the presence of another autoimmune disorder and over 30 percent with positive autoimmune serology. In classic work, Bias and coworkers (Am J Hum Genet 39:584-602, 1986) have shown that pedigrees ascertained on lupus and evaluated using humoral autoimmunity as an intermediate phenotype segregate this trait in an autosomal dominant pattern. We propose to use our now larger collection of pedigrees multiplex for SLE as a basis from which to seek evidence for the predicted autosomal dominant linkage as well as for other genetic effects. We will use our currently available collection of 173 pedigrees containing 1300 individuals to: 1) evaluate for a Lupus-Related Autoimmune (LRA) phenotype, 2) seek linkage, and 3) perform fine mapping in regions providing evidence for linkage. Identification of genes that govern the propensity to develop autoimmunity has potential to provide important insight into mechanisms of etiology and pathogenesis that are common among multiple autoimmune diseases. Understanding these underlying pathological events will lead towards new opportunities for development of more effective mechanism-based therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR046405-04
Application #
6375275
Study Section
Special Emphasis Panel (ZAR1-AAA-A (M1))
Program Officer
Serrate-Sztein, Susana
Project Start
1999-09-20
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2003-08-31
Support Year
4
Fiscal Year
2001
Total Cost
$74,250
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
Ramos, P S; Kelly, J A; Gray-McGuire, C et al. (2006) Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus. Genes Immun 7:417-32