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 #
5R01AR060861-02
Application #
8309039
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Wang, Yan Z
Project Start
2011-08-01
Project End
2012-10-09
Budget Start
2012-05-01
Budget End
2012-10-09
Support Year
2
Fiscal Year
2012
Total Cost
$351,000
Indirect Cost
$126,000
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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
Jensen, Mark A; Niewold, Timothy B (2015) Interferon regulatory factors: critical mediators of human lupus. Transl Res 165:283-95
Freedman, Barry I; Langefeld, Carl D; Andringa, Kelly K et al. (2014) End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol 66:390-6
Patterson, Karen C; Franek, Beverly S; Muller-Quernheim, Joachim et al. (2013) Circulating cytokines in sarcoidosis: phenotype-specific alterations for fibrotic and non-fibrotic pulmonary disease. Cytokine 61:906-11
Mangale, Dorothy; Kariuki, Silvia N; Chrabot, Beverly S et al. (2013) Familial aggregation of high tumor necrosis factor alpha levels in systemic lupus erythematosus. Clin Dev Immunol 2013:267430
Balboni, Imelda; Niewold, Timothy B; Morgan, Gabrielle et al. (2013) Interferon-? induction and detection of anti-ro, anti-la, anti-sm, and anti-rnp autoantibodies by autoantigen microarray analysis in juvenile dermatomyositis. Arthritis Rheum 65:2424-9
Jensen, Mark A; Patterson, Karen C; Kumar, Akaash A et al. (2013) Functional genetic polymorphisms in ILT3 are associated with decreased surface expression on dendritic cells and increased serum cytokines in lupus patients. Ann Rheum Dis 72:596-601
Chrabot, B S; Kariuki, S N; Zervou, M I et al. (2013) Genetic variation near IRF8 is associated with serologic and cytokine profiles in systemic lupus erythematosus and multiple sclerosis. Genes Immun 14:471-8
Niewold, Timothy B; Kelly, Jennifer A; Kariuki, Silvia N et al. (2012) IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Ann Rheum Dis 71:463-8
Agik, Sandra; Franek, Beverly S; Kumar, Akaash A et al. (2012) The autoimmune disease risk allele of UBE2L3 in African American patients with systemic lupus erythematosus: a recessive effect upon subphenotypes. J Rheumatol 39:73-8

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