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Genetic overlap among pediatric autoimmune diseases may point to shared therapies
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Genetic analysis of pediatric patients with 10 clinically distinct pediatric autoimmune diseases revealed overlapping genome-wide signals shared by at least two of the diseases, according to the results of a study.
Researchers studied the genetic data from 6,035 children of European descent with either 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 data were compared to a population-based control group of 10,718 participants also of European descent.
Hakon Hakonarson
Five novel genome-wide significant loci were identified: CD40LG, ADGRL2, TENM3, ANKRD30A and ADCY7. The researchers analyzed the single-nucleotide polymorphisms (SNPs) to uncover associations within each of 1,023 possible combinations of pediatric autoimmune diseases (pAIDs), including combinations of one, two, three and four of the 10 diseases.
Twenty-seven lead SNPs were identified, 22 of which were mapped to 77 different SNP-pAID combinations. Forty-four of the combinations had been previously reported as “at or near a genome-wide significance,” according to the study.
“Only five of the genes were identified are completely novel, in that they haven’t previously been associated with any disease," Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children's Hospital of Philadelphia (CHOP), told Healio.com/Rheumatology. “In others, we have identified multiple diseases. We knew one was related to Crohn’s disease, but now we can see it with ankylosing spondylitis as well.”
Hakonarson said existing therapies may be able to be repurposed.
“Many of these genes have been targeted for therapy for diseases other than autoimmune diseases,” Hakonarson said. “Some have been used to target cancer or infections. There is an opportunity to take existing drugs that have been shown to have a good safety profile in phase 3 trials but maybe weren’t effective in the problem it was being used to treat.”
While some of the variants identified were associated with only one disease, some of the alleles that conferred a higher risk for one disease were also associated with being protective against another. For example, PTPN22c.1858C>T was associated with the risk for T1D but appeared to be protective against Crohn’s Disease. Similar associations were seen with eight additional risk alleles. Nineteen variants were associated with at least three of the 10 pAIDs. No variants were associated with all 10 diseases.
In the future, it may be possible to identify which patient may or may not respond well to certain treatments, such as those which target specific tumor necrosis factor-alpha activity.
“We need to look at these types of associations and the variants in the genome,” Hakonarson said. “We need to sequence these regions and pull out the rare variants that appear to have more horsepower in the impact of disease, and then invite these patients to participate in clinical trials for drugs believed to target these regions that already have a known safety profile. It is possible that we could develop a quick proof-of-concept in patients with these specific mutations.” – by Shirley Pulawski
Disclosure: The researchers report no relevant financial disclosures.
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