Bruce Richardson, MD, PhD, University of Michigan Medical School

"Genetic/Epigenetic Modeling of Male Lupus Risk"

2009-2011 Male Lupus Research Grant Award

This grant award is made possible through support of the Wallace H. Coulter Foundation in memory of Michael Jon Barlin

Women develop lupus 9 times more often than men. Research implicates hormones and having 2 X chromosomes as part the problem in women. However, little is known about why men get lupus. Part of lupus susceptibility is genetically determined, and the genes responsible are being identified rapidly. However, not everyone with lupus genes gets lupus. Identical twin studies show that if one twin gets lupus, the other has a 24% chance of also getting lupus. This lack of complete concordance indicates that something from the environment is also required. Work from our group indicates that the environment contributes to lupus by modifying how DNA is packaged in the nucleus, referred to as chromatin structure. Genes in tightly packaged DNA cannot be expressed, but are expressed if the structure is opened up and available to the molecules causing expression. The primary signal for tight DNA packaging is a modification of DNA called methylation. Methylation serves to tether proteins that maintain the condensed structure. DNA methylation in regulatory immune cells, called T cells, is defective in people with lupus, and lupus can be caused in animal models just by inhibiting DNA methylation. We hypothesize that DNA demethylation in genetically predisposed people causes lupus. We also hypothesize that men will require more lupus genes, more DNA demethylation, or both to develop lupus than women. The studies proposed will test this model, and will lead to studies preventing lupus by maintaining DNA methylation, modifying genetic risk or both.