Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies against many self-antigens resulting in systemic blood vessel and target organ inflammation. Data from the available genome-wide microsatellite screens suggest that multiple genes contribute to the pathogenesis of SLE. Although classic linkage analysis is quite effective in identifying rare variants with a strong genetic effect, this approach has limited power to detect more common variants with modest penetrance. Thus, we hypothesize that many alleles important for the SLE phenotype will not be identified through genome screens. Our overall objective in the current proposal is to take a novel """"""""candidate pathway"""""""" association approach to the identification of genes and gene variants that contribute to SLE. SLE shows a striking female predominance with approximately a 10:1 female:male case ratio. Together with other data indicating an important role for sex steroids in the pathogenesis of SLE, we propose to examine coding region single nucleotide polymorphisms (SNPs) and the haplotype structure of 44 sex steroid pathway genes for evidence of association. For this, we will type our MN family collection, which currently is comprised of 250 sib-pair families, 300 trio families (single SLE patient with both parents), and a case control cohort of 300 cases and matched controls. Recent data from the Behrens laboratory have shown that about 70% of individuals with SLE carry a characteristic interferon-induced gene expression signature in their peripheral blood cells. Interestingly, this signature is observed in nearly all patients with the most severe type of lupus. We hypothesize that activation of the interferon pathway reflects allelic variation within the pathway that predisposes to disease. We will identify and then type coding SNPs and haplotypes within genes from this pathway for association with SLE. Finally, our group has recently identified a mutation in the CD40 gene that is strongly associated with SLE. CD40 is a key receptor on B cells and dendritic cells which is important for T-dependent immune and inflammatory responses. The identified mutation is a """"""""gain of-function"""""""" polymorphism that """"""""pre-loads"""""""" the cytoplasmic tail of CD40 with the signaling protein TRAF2. Cells carrying this mutation show altered signaling. We propose to screen additional molecules within the CD40 pathway, and other key members of the TNF receptor gene family, for additional polymorphisms associated with SLE. All putative associations will be replicated in a large cohort of 2,000 SLE cases and 2,000 controls. This project is a collaboration between the SLE genetics group at the University of Minnesota and the Broad Institute/Massachusetts General Hospital. The Broad Institute is one of the primary centers for the genome wide haplotype mapping (hap-map) project. Thus, the current study will have access to state-of-the-art methods for identification of relevant haplotypes, and for genotyping and data analysis. We anticipate that the proposed studies will lead to the identification of novel alleles that contribute to human SLE, and that this new knowledge will translate rapidly to better diagnosis and treatment of this important disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063274-06
Application #
7569999
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Johnson, David R
Project Start
2004-12-15
Project End
2011-11-30
Budget Start
2008-12-01
Budget End
2011-11-30
Support Year
6
Fiscal Year
2009
Total Cost
$730,678
Indirect Cost
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 :
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
Demirci, F Yesim; Wang, Xingbin; Kelly, Jennifer A et al. (2016) Identification of a New Susceptibility Locus for Systemic Lupus Erythematosus on Chromosome 12 in Individuals of European Ancestry. Arthritis Rheumatol 68:174-83
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
Lu, Xiaoming; Zoller, Erin E; Weirauch, Matthew T et al. (2015) Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression. Am J Hum Genet 96:731-9
Zhao, Jian; Wu, Hui; Langefeld, Carl D et al. (2015) Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus. Clin Immunol 161:157-62
Martins, M; Williams, A H; Comeau, M et al. (2015) Genetic association of CD247 (CD3?) with SLE in a large-scale multiethnic study. Genes Immun 16:142-50
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
Chung, Sharon A; Brown, Elizabeth E; Williams, Adrienne H et al. (2014) Lupus nephritis susceptibility loci in women with systemic lupus erythematosus. J Am Soc Nephrol 25:2859-70

Showing the most recent 10 out of 55 publications