Systemic lupus erythematosus (SLE) is a poorly understood autoimmune syndrome characterized by significant morbidity and mortality. Clinical trials in SLE have largely been unsuccessful, and improved understanding of disease heterogeneity and underlying pathogenic factors will be required for efficient intervention in the disease process. The pathogenesis of SLE is driven by a combination of genetic risk factors and environmental influences which lead to an irreversible break in immunologic self-tolerance. Recent genetic studies in SLE have identified numerous novel susceptibility loci, most of which have a modest overall effect on disease susceptibility (odds ratios 1.2-1.3). These studies have used a standard case-control design, studying very large cohorts at high cost. New approaches are needed, as the cohort size required to detect genes with odds ratios <1.2 increases exponentially, easily exceeding the current number of SLE samples available. The next major challenge in unraveling human SLE genetics lies in novel methods for gene discovery, as we are reaching the limit of feasibility with case-control designs. Many lines of evidence support the idea that increased interferon alpha (IFNa) pathway signaling is causal in human lupus. High serum IFNa is a heritable risk factor for SLE, and some established IFNa pathway SLE-risk genes are associated with higher serum IFNa in SLE patients. These data support the idea that gain-of-function variants in the IFNa pathway underlie SLE pathogenesis. Genetic studies of quantitative protein-level phenotypes are characterized by much greater statistical power for discovery than traditional case-control studies. In this proposal, we will use a number of novel techniques which employ IFNa as a quantitative trait to greatly increase the power of genetic analyses, enabling novel gene discovery in existing SLE cohorts. We will validate IFNa-associated candidate genes from a local case-case design genome- wide screen of SLE patients, re-analyze available SLE genome-wide single nucleotide polymorphism (SNP) data to detect associations with serum IFNa, and use gene expression databases to select and test candidate SNPs for association with serum IFNa in SLE patients. The IFNa pathway is one of the most consistently dysregulated causal pathways in human SLE, and defining the genetics of this pathway dysregulation will provide one of our best chances to define the molecular events underlying initial disease pathogenesis. Unmeasured heterogeneity in the molecular pathogenesis in SLE has likely limited the success of interventional drug trials to date. Detailed knowledge of the functional genetic factors present in a given patient could be of great utility in individualizing therapy, and may allow for the development of preventive strategies.

Public Health Relevance

Standard case-control study designs in the complex human disease lupus are reaching the limit of feasibility, as the cohort size required to detect genes with odds ratios for association lower than those currently known increases exponentially and easily exceeds the current number of SLE samples available. The IFNa pathway is one of the most consistently dysregulated causal pathways in human SLE, and defining the genetics of this pathway represents one of our best chances to provide insight into the molecular events underlying initial disease pathogenesis. In this proposal, we will use a number of novel techniques which employ IFNa as a quantitative trait to greatly increase the power of genetic analyses, enabling novel gene discovery in existing cohorts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR060861-05
Application #
8840888
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Wang, Yan Z
Project Start
2011-08-01
Project End
2016-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
5
Fiscal Year
2015
Total Cost
$413,266
Indirect Cost
$153,350
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Muskardin, Theresa L Wampler; Niewold, Timothy B (2018) Type I interferon in rheumatic diseases. Nat Rev Rheumatol 14:214-228
Ungprasert, P; Sagar, V; Crowson, C S et al. (2017) Incidence of systemic lupus erythematosus in a population-based cohort using revised 1997 American College of Rheumatology and the 2012 Systemic Lupus International Collaborating Clinics classification criteria. Lupus 26:240-247
Ghodke-Puranik, Yogita; Dorschner, Jessica M; Vsetecka, Danielle M et al. (2017) Lupus-Associated Functional Polymorphism in PNP Causes Cell Cycle Abnormalities and Interferon Pathway Activation in Human Immune Cells. Arthritis Rheumatol 69:2328-2337
Thanarajasingam, Uma; Jensen, Mark A; Dorschner, Jessica M et al. (2017) Brief Report: A Novel ELANE Mutation Associated With Inflammatory Arthritis, Defective NETosis, and Recurrent Parvovirus Infection. Arthritis Rheumatol 69:2396-2401
Loke, P'ng; Niewold, Timothy B (2017) By CyTOF: Heterogeneity of Human Monocytes. Arterioscler Thromb Vasc Biol 37:1423-1424
Sinicato, NailĂș AngĂ©lica; Postal, Mariana; Appenzeller, Simone et al. (2017) Defining biological subsets in systemic lupus erythematosus: progress toward personalized therapy. Pharmaceut Med 31:81-88
Iwamoto, Taro; Niewold, Timothy B (2017) Genetics of human lupus nephritis. Clin Immunol 185:32-39
Niewold, Timothy B (2016) Connective tissue diseases: Targeting type I interferon in systemic lupus erythematosus. Nat Rev Rheumatol 12:377-8
Wampler Muskardin, Theresa; Vashisht, Priyanka; Dorschner, Jessica M et al. (2016) Increased pretreatment serum IFN-?/? ratio predicts non-response to tumour necrosis factor ? inhibition in rheumatoid arthritis. Ann Rheum Dis 75:1757-62
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

Showing the most recent 10 out of 39 publications