The major histocompatibility complex (MHC) is the dominant region of association in SLE from European- derived subjects. In initial SLEGEN genome wide analyses, 86 SNPs spanning 6.4 Mb reached genome wide Statistical evidence at p<10-6. Combined with a replication cohort, analyses involving 5,278 samples reaches impressive significance levels (p<10-44). Multiple effects within this large region are strongly suggested by these and other data and will be further characterized. The large multiracial collection assembled by SLEGEN is a particular strength for this project. We will use the obvious population differences in the MHC to separate and isolate individual genomic elements containing causative polymorphisms. We have the following specific Aims:
Aim 1 : Perform a meta-analysis of available high density MHC datasets to more precisely define the locations and extent of genetic effects within the MHC among European-derived populations. Prediction: At least two separate associations in the MHC region will be convincingly established and characterized in.the European-derived sample.
Aim 2 : Define the region and extent of genetic effects across the MHC in populations of non-European origin (i.e. African-Americans, Hispanics and Asians). Prediction: Analysis of additional ethnic groups will facilitate narrowing of associated regions within the MHC due to population substructure differences in MHC haplotypes. Synergies: All of the other Projects will be very important for the success of this Aim.
Aim 3 : Perform association analyses in subgroups defined by specific SLE disease features. We will examine more homogeneous subgroups as a strategy to further separate the genetic effects within the MHC region, including subsets defined by specific autoanfibodies or clinical variables such as nephritis. Prediction;Particular sub-phenotypes will be less genetically heterogeneous and will provide increased statistical power to more precisely define genotype-phenotype correlations and decipher individual effects within the MHC region.

Public Health Relevance

The MHC represents the most important genetic contribution to SLE for European-derived populations, however prior work has not fully defined the specific causal variants. There is a paucity of data for non- European populations in spite of the excess burden of disease among these groups. A thorough delineation of the MHC contribufion to SLE will be crucial to fully understand the role of other causal variants.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oklahoma Medical Research Foundation
Oklahoma City
United States
Zip Code
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
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
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
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 68:1197-1209
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
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
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
Zhao, Jian; Wu, Hui; Langefeld, Carl D et al. (2015) Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus. Clin Immunol 161:157-62
Martins, M; Williams, A H; Comeau, M et al. (2015) Genetic association of CD247 (CD3?) with SLE in a large-scale multiethnic study. Genes Immun 16:142-50

Showing the most recent 10 out of 78 publications