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Many Pediatric Autoimmune Disorders Share Altered Genetic Loci, Study Finds

NEW YORK (GenomeWeb) – Many pediatric autoimmune disorders have genetic alterations at shared sites, according to a meta-analysis performed by researchers from Children's Hospital of Philadelphia and elsewhere.

The researchers conducted a meta-analysis of 10 childhood-onset autoimmune diseases — such as inflammatory bowel disease, type 1 diabetes, and juvenile idiopathic arthritis, among others — to uncover 22 loci that were shared among multiple pediatric autoimmune diseases, as they reported today in Nature Medicine. The researchers traced these signals to genes involved in immune-related pathways like cell activation, cell proliferation, and signaling.

"Our approach did more than [find] genetic associations among a group of diseases," senior author Hakon Hakonarson, the director of the Center for Applied Genomics at CHOP, said in a statement. "We identified genes with a biological relevance to these diseases, acting along gene networks and pathways that may offer very useful targets for therapy."

Hakonarson and his colleagues performed whole-genome imputation on a combined cohort of 6,035 pediatric cases, representing 10 distinct autoimmune diseases, and 10,718 population-based controls with no history of immune disorders. From this, they found more than 7.3 million variants.

Using case samples from each of the 10 conditions and shared controls, they performed whole-genome case-control association testing, and then to find shared loci among the pediatric-onset autoimmune diseases they performed an inverse χ2 meta-analysis, which they said took into consideration both variations in sample sizes and their use of a shared cohort.

From this analysis, they identified 27 linkage disequilibrium-independent loci with genome-wide significance among the conditions, including five novel loci.

Twenty-two of these loci, the researchers reported, were shared among multiple pediatric autoimmune diseases. For instance, a locus mapping to an intronic SNP in IL21 was shared by eight conditions, while a novel loci in TENM3 was shared by six conditions.

The SNPs Hakonarson and his colleagues uncovered fell into four broad categories: functional, regulatory, conserved, and SNPs with prior literature support connecting them to an autoimmune disorder.

The vast majority of the SNPs, they said, don't appear to directly have functional consequences — they noted the SNPs were enriched for CpG islands, transcription factor binding sites, and more — suggesting that they either tag the causal variants or influence disease risk through regulatory or epigenetic mechanisms.

Using gene-based association testing, the researchers found 182 pediatric autoimmune disease-related genes. By examining a human gene expression microarray dataset of 12,000 genes and 126 tissue or cell types, the researchers observed that these genes were more highly expressed in immune cells than non-immune cells. They further discovered that these pediatric autoimmune disease-related genes were differentially expressed across immune cell types.

Based on their expression profiles, the researchers clustered the genes into related sets.

Cluster one, for instance, included ICAM1, CD40, JAK2, TYK2, and IL12B, which have roles in immune effector cell activation and proliferation. These genes were also associated with both primary sclerosing cholangitis and ulcerative colitis. The expression of these genes was higher in a subset of CD11b+ dendritic cells. This, Hakonarson and his colleagues said, is consistent with the clinical picture, as some 80 percent of primary sclerosing cholangitis patients have also been diagnosed with ulcerative colitis.

Similarly, cluster two genes were related to cytokines and were highly expressed across mature natural killer cells. The cluster was enriched for associations with multiple sclerosis and celiac disease, the researchers added.

Hakonarson and his colleagues developed a method to examine genome-wide pairwise-association signal sharing — dubbed a GPS test — across the various pediatric autoimmune conditions. The test, they reported, found evidence of sharing among type 1 diabetes and celiac disease; type 1 diabetes and autoimmune thyroiditis; ulcerative colitis and Crohn's disease; and ankylosing spondylitis and psoriasis, associations they said had been reported previously. They also uncovered evidence of sharing among juvenile idiopathic arthritis and common variable immunodeficiency.

Using ImmunoBase, they also found evidence of sharing between ulcerative colitis and Crohn's disease as well as between juvenile idiopathic arthritis and common variable immunodeficiency.

"Collectively, these results support genetic sharing between the various autoimmune diseases," the researchers said in their paper.

Hakonarson and his colleagues added that knowing that certain diseases have a shared genetic etiology could point to common mechanisms that could be targeted by a therapeutic. Further, they noted that a number of the genes they identified are already being explored clinically.

This study "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," Hakonarson added.