Systemic lupus erythematosus is a chronic relapsing autoimmune disease that involves multiple organ systems. The etiology and pathogenesis of lupus are incompletely understood. There is a strong evidence for genetic contribution to the pathogenesis of lupus, however, despite the enormous progress in mapping lupus susceptibility genes, only a small fraction of lupus heritability is accounted for by the genetic associations discovered. A large body of literature supports the contention that epigenetic dysregulation, particularly T cell DNA methylation defect, contributes to the pathogenesis of lupus. Indeed, demethylated T cells are sufficient to cause lupus in animal models. We believe that epigenetic differences between lupus patients and controls contribute towards the "missing" heritability of the disease. We propose to determine and functionally characterize differentially methylated genetic loci in specific T cell subsets in lupus patients compared to normal controls, using a genome-wide approach, the feasibility of which has been confirmed in our own preliminary experiments. We will further Identify and validate DNA methylation changes over time in relation to disease activity in lupus patients. We hypothesize that genetic variants associated with lupus will alter DNA methylation in known lupus susceptibility loci in an allele-specific manner. Therefore, we will determine allele specific DNA methylation changes in validated genetic susceptibility loci for lupus. We previously reported the genetic association between SNPs within MECP2 and lupus. MECP2 (methyl-CpG-binding protein 2) is a key transcriptional regulator for methylation sensitive genes, and is also known to recruit the DNA methylation enzyme DNMT1 during DNA synthesis. We will resequence the MECP2/IRAK1 LD block using next generation sequencing to identify the causal variants in this locus.

Public Health Relevance

Lupus is a chronic systemic autoimmune disease that causes significant morbidity and mortality in those affected. Therapies still rely largely on relatively nonspecific approaches that have potentially serious side effects. There is evidence for genetic and epigenetic contribution to the pathogenesis of lupus. Our studies will identify and functionally characterize the DNA methylation differences in specific CD4+ T cell subsets between lupus patients and controls, and will determine DNA methylation changes over time in relation to disease activity in lupus patients. We will also study genetic-epigenetic interaction i lupus through allele-specific methylation studies and through the identification of the causal variant(s) in MECP2, a gene that regulates the expression of methylation sensitive genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI097134-01A1
Application #
8503129
Study Section
Special Emphasis Panel (ZRG1-MOSS-T (02))
Program Officer
Johnson, David R
Project Start
2013-02-25
Project End
2018-01-31
Budget Start
2013-02-25
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$374,747
Indirect Cost
$133,752
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109