We propose to define the complex role of genes within the major histocompatability complex (MHC) region on chromosome 6p21 in systemic lupus erythematosus (SLE) pathogenesis. Our study design is based on the overall hypothesis that complex genetic and non-genetic MHC related mechanisms, including effects conferred by classical HLA loci, contribute to both disease risk and clinical outcome. It is clear that the genetic contribution of the MHC to SLE is substantial, with HLA class II genes demonstrating the most prominent association. However, the extensive linkage disequilibrium in the region and incomplete knowledge of allelic variation in surrounding genes has been a major limiting factor in attempts to further define the genetic contribution of the MHC to SLE. Through the recent efforts of the MHC Haplotype Project, all genes encoded within the approximately 4.5 Mb MHC region have been identified and localized, and are now publicly available, providing an unparalleled molecular guide for deciphering the MHC contribution to SLE. It is also evident that additional mechanisms such as genomic imprinting and non-inherited or environmental influences are likely to be involved in susceptibility to complex diseases such as SLE. Using 1,000 stringently ascertained and clinically characterized SLE families, state of the art genotyping methodologies, and novel analytical approaches we propose for the first time a comprehensive study of all genes residing within the MHC. In addition, we will investigate potential imprinting and maternal-fetal relationships in these families to determine whether MHC encoded loci and specific HLA alleles or haplotypes influence the risk of SLE. These studies will unequivocally identify the genes and allelic variants residing in the MHC region involved in susceptibility to SLE. Further, due to the strong relationship of lupus nephritis to SLE morbidity and mortality, in conjunction with data supporting distinct genetic associations with this outcome, we will study lupus nephritis as an important secondary outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052300-02
Application #
7053348
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Serrate-Sztein, Susana
Project Start
2005-04-10
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$571,633
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Mok, Amanda; Solomon, Olivia; Nayak, Renuka R et al. (2016) Genome-wide profiling identifies associations between lupus nephritis and differential methylation of genes regulating tissue hypoxia and type 1 interferon responses. Lupus Sci Med 3:e000183
Kottyan, Leah C; Zoller, Erin E; Bene, Jessica et al. (2015) The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share. Hum Mol Genet 24:582-96
Chung, Sharon A; Nititham, Joanne; Elboudwarej, Emon et al. (2015) Genome-Wide Assessment of Differential DNA Methylation Associated with Autoantibody Production in Systemic Lupus Erythematosus. PLoS One 10:e0129813
Armstrong, D L; Zidovetzki, R; Alarcón-Riquelme, M E et al. (2014) GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region. Genes Immun 15:347-54
Morris, D L; Fernando, M M A; Taylor, K E et al. (2014) MHC associations with clinical and autoantibody manifestations in European SLE. Genes Immun 15:210-7
Chung, Sharon A; Brown, Elizabeth E; Williams, Adrienne H et al. (2014) Lupus nephritis susceptibility loci in women with systemic lupus erythematosus. J Am Soc Nephrol 25:2859-70
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
Wang, Chuan; Ahlford, Annika; Järvinen, Tiina M et al. (2013) Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations. Eur J Hum Genet 21:994-9
Sánchez, Elena; Rasmussen, Astrid; Riba, Laura et al. (2012) Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian-European populations. Arthritis Rheum 64:3687-94
Sacre, Karim; Criswell, Lindsey A; McCune, Joseph M (2012) Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther 14:R155

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