Genetic Overlapping in IBD, Other Autoimmune Diseases May Suggest Potential For Common Therapies

Genetic Overlapping in IBD, Other Autoimmune Diseases May Suggest Potential For Common Therapies

A team of scientists led by Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia (CHOP) Center for Applied Genomics in a major meta-analysis of the genes involved in 10 autoimmune diseases that begin in childhood, have discovered 22 genome-wide signals shared by two or more of these diseases such as type 1 diabetes, Crohn’s disease, and juvenile idiopathic arthritis that collectively affect 7 to 10 percent of the population in the Western Hemisphere, respectively. These shared gene sites may be key to revealing potential new targets for treating many of these diseases, in some instances with existing drugs already available for non-autoimmune disorders.

“Our approach did more than finding genetic associations among a group of diseases, says study leader Dr. Hakonarson.”We identified genes with a biological relevance to these diseases, acting along gene networks and pathways that may offer very useful targets for therapy.”

Study results published in the journal Nature August 24, entitled Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases (Nature Medicine (2015) dpi:10.1038/nm.3933) are coauthored by an international, multi-institutional team of investigators, who observe that genome-wide association studies (GWAS) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases.

The scientists describe how they performed an inverse meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based 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.

“We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silicoreplicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG,” the coauthors explain. “We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.”

The Pathogenic Role Of Genes Across Diseases

The 10 clinically distinct autoimmune diseases with onset during childhood focused on by the investigative team included: 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.

Because many of these diseases tend to run in families and because individual patients often have more than one autoimmune condition, clinicians have long suspected that these various disorders have genetic predispositions in common, with previous genome-wide association studies having identified hundreds of susceptibility genes among autoimmune diseases, largely affecting adults.

In the systematic analysis of multiple pediatric-onset diseases simultaneously reported in the Nature paper, the study team 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, with 19 shared by at least three of them.

Biological Pathways Linked To Cell Activation, Proliferation And Signaling

Many of the gene signals the investigators discovered were found on biological pathways functionally linked to cell activation, cell proliferation and signaling systems associated with immune processes. One of the five novel signals, near the CD40LG gene, was especially compelling, says Dr. Hakonarson in a CHOP release, observing: “That gene encodes the ligand for the CD40 receptor, which is associated with Crohn’s disease, ulcerative colitis and celiac disease. This ligand may represent another promising drug target in treating these diseases.”

“Many of the 27 gene signals the investigators uncovered have a biological relevance to autoimmune disease processes,” explains Dr. Hakonarson, who is also a member of the faculty of the Perelman School of Medicine at the University of Pennsylvania. “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. 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.”

Dr. Hakonarson adds that the level of granularity the study team uncovered offers opportunities for researchers to better target gene networks and pathways in specific autoimmune diseases, and perhaps to fine tune and expedite drug development by repurposing existing drugs, based on our findings.

Funds from the National Institutes of Health (grants DK085708, AR058606, HG006830, CA127334, and HG006849), the Wellcome Trust, the Paul and Daisy Soros Fellowship for New Americans, the Crohns & 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.

Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases, Nature Medicine, published online Aug. 24, 2015:

The Children’s Hospital of Philadelphia (CHOP)
Center for Applied Genomics
Journal of Young Investigators

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The Children’s Hospital of Philadelphia (CHOP)
Journal of Young Investigators