New evidence of shared genetic variations between different pediatric onset autoimmune diseases (pAIDs) may open the door to targeted therapies, according to a study published online August 24 in Nature Medicine.
"We have identified multiple risk variants that predispose to autoimmunity in children. These variants reside in many genes that are previously known drug targets, and there are molecules/drugs in various stages of development for different diseases or disorders," said senior author Hakon Hakonarson, MD, PhD, the director of the Center for Applied Genomics.
"Our goal is to take those forward and test them in patients who harbor these variants for proof of concept," he told Medscape Medical News.
In a genome-wide meta-analysis of 10 pediatric-onset autoimmune diseases, investigators from the Children's Hospital of Philadelphia uncovered 27 disease-susceptibility loci, including five novel loci. Of the 27 signals, 22 (81%) were shared by at least two of the autoimmune diseases, and 19 (70%) of them were shared by at least three diseases, lead author Yun Li, a graduate student at the University of Pennsylvania and the Children's Hospital of Philadelphia Center for Applied Genomics, and colleagues report.
The investigators analyzed data from a case-control study including more than 6035 pAID patients and 10,718 population-based control participants. The 10 clinically distinct pAIDs included in the analysis were 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 traced the identified signals to genes known to be involved in various immune-related pathways, including cytokine signaling, antigen processing and presentation, T-cell activation, JAK-STAT activation, and TH1-, TH2-, and TH17-associated cytokine signaling.
"Of these pathways, JAK2 signaling was particularly compelling," the authors write, noting that this finding is consistent with the enrichment of known protein–protein interactions. "We also uncovered evidence supporting shared genetic susceptibility for disease pairs that have not yet been well established."
The observed association between juvenile idiopathic arthritis and common variable immunodeficiency disease, in particular, "is noteworthy, given that [common variable immunodeficiency disease] actually represents a group of complex immunodeficiencies rather than a classic autoimmune disease," they add.
In essence, this type of insight will enable the personalization of therapies across multiple different diseases based on the genetic underpinnings of each patient, Dr Hakonarson told Medscape Medical News.
"Essentially, it is a form of molecular phenotyping…. It would be anticipated that the subset of patients who harbor risk variants in gene 1 may be more likely to respond to drug A, independent of which autoimmune disease they have, whereas patients with risk variants in gene 2 may be more likely to respond to drug B, independent of the type of autoimmune disease they have, and so forth," he explained.
The findings also have clinical relevance for current patient care. "They allow us to think about patients with different autoimmune diseases more as subgroups or cohorts of individuals with specific variants," Dr Hakonarson said.
"Some have TH1 cytokine drivers for their disease, others have TH2 drivers, yet others TH17 drivers. We have therapies available today to modulate these specific cytokines/pro-inflammatory mediators more specifically than others. These would be therapies of choice until we develop the most optimized and robust molecules, or repositioned them from other therapeutic areas for this purpose," he added.
The authors have disclosed no relevant financial relationships.
Nature Med. Published online August 24, 2015. Full text
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Cite this: Multiple Autoimmune Diseases Share Same Genetic Risk Factors - Medscape - Sep 04, 2015.