Systemic lupus erythematosus (SLE) is often severe, causing nephritis, oral ulcers, arthritis, pericarditis, pleuritis, rashes, strokes, heart attacks, vasculitis, nervous dysfunction, cytopenias, Raynaud's disease, and immune dysfunction. SLE has complex genetics with many genes contributing to the phenotype. This project, AI242717, has established or confirmed 17 different robust genetic effects, including two susceptibility genes. The centerpiece of the competitive renewal is to identify the gene responsible for the autosomal dominant linkage at 5ql4 with SLE in pedigrees containing an SLE affected with autoimmune thyroid disease. This linkage has been established (LOD=4.96) and independently confirmed (LOD=3.15), thereby providing convincing evidence for linkage. The optimal combined twopoint LOD=9.95. Linkage at 5ql4 has been previously reported in autoimmune thyroid disease. We have explored 599 SNPs for association in the linkage interval and have identified a strong candidate gene. Though there much work left to do, the available evidence is particularly convincing (by repetition and independent replication) that a group of markers, spanning 22 kb and presumed to be in linkage disequilibrium with the causative variant(s) of the candidate gene, is strongly associated with SLE. There are many thousands of untested SNPs in the 5ql4 linkage interval from 91 mb to 100 mb available to help find genetic association if subsequent results do not continue to support candidate gene involvement, including 2051 dbSNPs. We plan to identify the candidate gene variants associated with SLE. In addition, four different confirmatory patient groups are available to test the association, hopefully reinforcing unambiguous gene identification. If this project is successful, then the responsible gene at 5ql4 will have been convincingly identified. We will explore the properties of the responsible gene to describe functional variations that work through this gene to generate SLE. Once this work with the responsible gene at 5ql4 is complete we will redeploy the experimental capacity of AI24717 to explore the next most promising linkage. At this time, a linkage at 3p21 found twice, in pedigrees with SLE cigarette smokers and in SLE pedigrees with anti-Ro and anti-La autoantibodies, is the next most convincing. As suggested by the reviewers, other previously presented specific aims have been removed from the resubmitted AI24717-17A1 proposal. The identified genes and resulting more complete genetic model of lupus will provide better understanding of the pathophysiology of lupus, improved prognostic tools for disease assessment in lupus as well as, perhaps, in other autoimmune diseases, and new molecular targets for therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37AI024717-22
Application #
7674853
Study Section
Special Emphasis Panel (NSS)
Program Officer
Johnson, David R
Project Start
1987-07-01
Project End
2010-09-06
Budget Start
2010-03-04
Budget End
2010-09-06
Support Year
22
Fiscal Year
2010
Total Cost
$115,910
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Aberle, Teresa; Bourn, Rebecka L; Chen, Hua et al. (2017) Use of SLICC criteria in a large, diverse lupus registry enables SLE classification of a subset of ACR-designated subjects with incomplete lupus. Lupus Sci Med 4:e000176
Aberle, Teresa; Bourn, Rebecka L; Munroe, Melissa E et al. (2017) Clinical and Serologic Features in Patients With Incomplete Lupus Classification Versus Systemic Lupus Erythematosus Patients and Controls. Arthritis Care Res (Hoboken) 69:1780-1788
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
Taylor, Rhonda L; Cruickshank, Mark N; Karimi, Mahdad et al. (2016) Focused transcription from the human CR2/CD21 core promoter is regulated by synergistic activity of TATA and Initiator elements in mature B cells. Cell Mol Immunol 13:119-31
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
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
Lu, Rufei; Munroe, Melissa E; Guthridge, Joel M et al. (2016) Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies. J Autoimmun 74:182-193
Munroe, Melissa E; Lu, Rufei; Zhao, Yan D et al. (2016) Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification. Ann Rheum Dis 75:2014-2021
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
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

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