SP0104 The Molecular Basis of Autoimmune Disease

Genome-wide association studies have identified numerous genetic associations between common SNPs and risk of autoimmune diseases, some of which are shared between diseases. Along with clinical evidence, this suggests that some genetic risk factors with their biologic effects may be shared across diseases. We evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases and developed a novel statistic for Cross Phenotype Meta-Analysis which detects association of a SNP to multiple, but not necessarily all, phenotypes. We find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple – but not all – immune-mediated diseases (SNP-wise P CPMA< 0.01). Distinct groups of interacting proteins are encoded near SNPs that predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We have begun efforts to identify the biologic effects of disease causing SNPs at non-coding regions of the genome where it has been difficult to assign function to DNA sequence and to compare these effects across different autoimmune diseases. We use fine-mapping genetic data to identify causal mutations and integrate these data with chromatin maps of ten defined human CD4+ T-cell populations. These investigations identified risk variants disrupting the enhancers of distinct cell types among the different autoimmune diseases, particularly in AP-1 and NFkB. Finally, autoimmune disease results from untoward interactions between genetics and the environment. We recently showed that increased salt (NaCl) concentrations found locally under physiological conditions in vivo dramatically boost the induction of Th17 cells mediated by SGK1. The Th17 cells generated under high-salt display a highly pathogenic and stable phenotype characterized by the up-regulation of the pro-inflammatory cytokines GM-CSF, TNFα and IL-2. Recent data revealed that higher NaCl levels also decreased the function of human CD4+CD25+FoxP3+ Tregs isolated ex vivo. Mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen specific Th17 cells. It was of interest to observe that RNA array analyses of genes induced by NaCl were markedly enhanced among GWAS hits. Identifying specific sites where a single, non-coding nucleotide variant is responsible for disease risk may pinpoint specific disruptions of consensus transcription