Although the 'reverse genetics'approach has associated SLE disease risk with several genes with known immune function including complement proteins, antibody receptors and immune signaling molecules, the newly developed ability to scan the entire genome provides an unprecedented opportunity for novel discovery of critical pathways in disease pathogenesis. SLEGEN, a productive multi-institutional consortium of lupus investigators, matches the capacity for current state-of-the-art genome-wide technology with large phenotypically characterized participant collections which provide appropriate statistical power for genomewide studies. SLEGEN has successfully conducted a genome wide association study (GWAS) with independent replication in European-derived populations and has both confirmed previous candidate genes and discovered multiple new genetic effects. As a result of SLEGEN, and the work of others, the genetic variants known to contribute to the risk of lupus now include ITGAM (CDI lb, CR3), STAT4, BANKl, BLK, HLA-DR, IRF5, FCGR3A, FCGR2A, Clq, Complement C4, and PTPN22, among others. However, both the phenotypic variation in other populations with different ancestries and initial data indicate that not all European variants have similar roles in these populations and that we have much to learn about the genetic architecture of human lupus. A trans-racial mapping approach provides a unique opportunity to identify both variants in common and variants which may be population specific. SLEGEN is uniquely positioned to take advantage of this opportunity. Project 1 will explore the HLA region variation in >6000 subjects who are African-American, Amerindian admixed Hispanics, or Asians and grounded at HLA-DRB2 using existing genome data for European-derived subjects. Projects 2-4 will explore the whole genome by evaluating 1.8 million markers in 6000 non-European subjects with replication, fine mapping, and trans-racial mapping in 9000 additional subjects. This will be the largest genomic exploration attempted in lupus, and in aggregate, will benefit from genetic data assembled from >27,000 cases and controls. These experiments are highly interdependent, relying upon inferences in one population group for perspective and interpretation in the others. The resulting level of understanding promises to establish the genetic etiology of lupus, spawn new diagnostics, prognostics, and therapeutics which provide therapeutic benefit to this and many related illnesses.

Public Health Relevance

Systemic lupus erythematosus (SLE) is a debilitating, often life-threatening and sometimes deadly inflammatory disease. Autoimmunity, complement activation, and interferon abnormalities are common themes in pathogenesis. Lupus is hereditary and while progress has clearly been made, the potential for discovery in non-European populations is great. These genes form the basis for understanding pathogenesis making them the foundation upon which are built nevtf diagnostics and therapeutics to combat this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI083194-05
Application #
8514477
Study Section
Special Emphasis Panel (ZAI1-KS-I (M1))
Program Officer
Johnson, David R
Project Start
2009-08-15
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$1,804,281
Indirect Cost
$277,693
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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
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
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
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
Lessard, Christopher J; Sajuthi, Satria; Zhao, Jian et al. (2016) Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans. Arthritis Rheumatol 68:1197-209
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
Alarcón-Riquelme, Marta E; Ziegler, Julie T; Molineros, Julio et al. (2016) Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture. Arthritis Rheumatol 68:932-43
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 68:1290-300
Kariuki, S N; Ghodke-Puranik, Y; Dorschner, J M et al. (2015) Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus. Genes Immun 16:15-23
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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