Systemic lupus erythematosus (SLE) is a complex, partially understood autoimmune disease that affects 300,000 Americans. In African-American women, SLE has been estimated to occur as frequently as 1 in every 250. African-Americans have a higher incidence and prevalence of lupus by about 3.5-fold compared to European-derived peoples. Understanding the mechanisms of lupus is imperative if we have any hope of finding therapies that will safely treat this disease. We cannot fully understand lupus without explaining its genetic architecture. Genes that alter risk are origins of disease causation and must be involved in disease pathogenesis. Many strategies are now available to discover these genes. Candidate gene approaches have given way to reverse genetics and the possibility of evaluating the entire genome has very recently undergone a technical scientific revolution providing the capacity to evaluate over 1 million markers per individual subject. In Project 2, we will evaluate the genomics of lupus in African-Americans by exploiting the new technologies and applying a genome-wide association scan in 1,400 cases and 400 controls on the Affymetrix 6.0 array. We will also have genotype data from an additional 1,000 African-American out-of-study controls already typed on the Affymetrix 6.0 array, giving us 80% power to detect odds ratios >1.38 when applying a threshold of p=5xl0E-8. We will further explore powerful hits in a large replication experiment of ~15,000 SNPs in 9,000 subjects of African-American, Hispanic and Asian descent. We will physically define the genomic interval containing the association effect using the trans-racial and fine mapping approaches. We will construct haplotypes and apply standard regression methods to identify and characterize genetic effects. We will use resequencing to identify novel variants. The candidate polymorphisms and their surrogates will be evaluated for genomic mechanism(s). When successfully completed this POI project will provide new genes with fundamental insights into the mechanisms by which lupus is generated. At the same time the infrastructure developed through this POI will provide the basis from which to evaluate compelling candidate genes important for lupus in minority populations.

Public Health Relevance

Systemic lupus erythematosus (SLE) is a debilitating and often life-threatening disease, particulariy in African-Americans. Most progress to date has been in European populations. We have the opportunity with this P01 to better undersand lupus in African-Americans. The knowledge gained will form the basis for understanding the pathogenesis of this disorder, leading to new, safer, and more specific therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI083194-05
Application #
8514480
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$278,471
Indirect Cost
$42,859
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

Showing the most recent 10 out of 80 publications