Gene Sites Shared Across Multiple Pediatric Autoimmune Diseases

Many autoimmune diseases run in families, and because individual patients often have more than one autoimmune condition, clinicians have long suspected that these disorders have shared genetic predispositions. An international study team led by researchers from The Children’s Hospital of Philadelphia’s Center for Applied Genomics focused on 10 autoimmune diseases that begin in childhood and found that they indeed have genetic overlaps.

Autoimmune diseases occur when they body’s immune system attacks and destroys healthy body tissue by mistake. More than 80 types of autoimmune disorders exist, and they collectively affect 7 to 10 percent of the Western Hemisphere’s population. The current research encompassed 10 pediatric autoimmune diseases: type 1 diabetes, celiac disease, juvenile idiopathic arthritis, common variable immunodeficiency disease, systemic lupus erythematosus, Crohn’s disease, ulcerative colitis, psoriasis, autoimmune thyroiditis, and ankylosing spondylitis.

The investigators found 27 genome-wide loci, including five novel loci, among the diseases examined. Of those 27 signals, 22 were shared by at least two of the autoimmune diseases, and 19 of them were shared by at least three of them. The results appeared online in Nature Medicine.

“Our approach did more than finding genetic associations among a group of diseases,” said study leader, Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at CHOP. “We identified genes with a biological relevance to these diseases, acting along gene networks and pathways that may offer very useful targets for therapy.”

The meta-analysis included a case-control study of 6,035 subjects with automimmune disease and 10,700 controls, all of European ancestry. The study’s lead analyst, Yun (Rose) Li, an MD/PhD graduate student at the University of Pennsylvania and the Center for Applied Genomics mentored by Dr. Hakonarson and his research team, applied highly innovative and integrative approaches in supporting the study of pathogenic roles of the genes uncovered across multiple diseases.

“Rather than looking at overall gene expression in all cells, we focused on how these genes upregulated gene expression in specific cell types and tissues, and found patterns that were directly relevant to specific diseases,” said Dr. Hakonarson, who also is on the faculty of the Perelman School of Medicine at the University of Pennsylvania. “For instance, among several of the diseases, we saw genes with stronger expression in B cells. Looking at diseases such as lupus or juvenile idiopathic arthritis, which feature dysfunctions in B cells, we can start to design therapies to dial down over-expression in those cells.”

Many of the gene signals the investigators discovered were on biological pathways functionally linked to cell activation, cell proliferation, and signaling systems important in immune processes. Identifying specific autoimmune diseases’ genetic architecture gives researchers opportunities to better target potential therapies, including the possibility of repurposing existing drugs available for non-autoimmune diseases.

Funds from the National Institutes of Health, the Wellcome Trust, the Paul and Daisy Soros Fellowship for New Americans, the Crohn’s & Colitis Foundation of America, the Juvenile Diabetes Research Foundation, the Lupus Research Institute, and Institutional Development Funds from The Children’s Hospital of Philadelphia supported this research.