Researchers have determined the heritability and genetic sharing of 9 pediatric autoimmune diseases, according to a study published in Nature Communications.1
Type 1 diabetes and juvenile idiopathic arthritis had the highest rates of heritability among pediatric populations, and the pairings of ulcerative colitis/Crohn’s disease and juvenile idiopathic arthritis/common variable immunodeficiency disorder were most strongly correlated.
The study included 9 pediatric autoimmune diseases: Crohn’s disease, celiac disease, common variable immunodeficiency disorder, epilepsy, juvenile idiopathic arthritis, psoriasis, systemic lupus erythematosus, spondyloarthropathy, type 1 diabetes, and ulcerative colitis.
The researchers quantified narrow-sense or additive heritability (h2) of each disease through genome-wide, single-nucleotide polymorphism (SNP) genotyping data, referred to as SNP-based heritability (SNP-h2). They obtained this genome data from DNA samples from both pediatric autoimmune disease cohorts and population-based controls.
The pediatric autoimmune disease that had the most significant SNP-h2 estimates were type 1 diabetes (0.863 ± SE 0.07) and juvenile idiopathic arthritis (0.727 ± SE 0.037). SNP-h2 was more modest for ulcerative colitis (0.386 ± SE 0.04) and Crohn’s disease (0.454 ± SE 0.025), which may suggest that environmental factors play a larger role in these diseases. These findings are consistent with population estimates, though they are larger than previous evidence from adult genome-wide association studies.
Through pairwise analysis, the researchers found that ulcerative colitis and Crohn’s disease (0.69 ± SE 0.07) were most strongly correlated, followed by juvenile idiopathic arthritis and common variable immunodeficiency disorder (0.343 ± SE 0.13).
Systemic lupus erythematosus (SLE) showed relatively low heritability, suggesting its etiology is influenced more heavily by environmental and epigenetic factors.
The researchers hope that these results can help identify potential biomarkers for pediatric autoimmune diseases.
Summary and Clinical Applicability
The demonstration of autoantibodies is usually the first step in the diagnosis of an autoimmune disease. Like all immune responses, autoimmunity is under strict genetic control of antigen recognition, cellular interactions, and eventual outcomes.
In this study, SLE showed relatively low heritability.1 Genome-wide association studies (GWAS) have identified approximately 50 gene loci with polymorphisms (or, rarely, mutations or copy numbers) that predispose to SLE2. However, this genetic information accounts for only 18% of susceptibility to SLE. A combination of susceptibility genes, or presence of susceptibility genes plus the absence of protective genes are required for sufficient genetic susceptibility to permit disease development, and it is likely that environmental or epigenetic changes play a major role.
Genetic factors that do confer the highest hazard ratios (HR) of 5 to 25 are deficiencies of the complement components C1q (required to clear apoptotic cells), C4A and B, C2, or the presence of a mutated TREX1 gene (encodes the three prime repair endonuclease1 enzyme that degrades DNA). Each of these is relatively rare in the population.3 The most common genetic predisposition is found at the major histocompatibility (MHC) locus. The MHC contains genes for antigen presenting molecules (class I human leukocyte antigens [HLA-A, -B, and -C] and class II HLA molecules [HLA-DR, -DQ, and DP]).4
1. Li YR, Zhao SD, Li J, et al. Genetic sharing and heritability of paediatric age of onset autoimmune diseases. Nature Communications. 2015;6:8442.
2. Rullo OJ, Tsao BP. Recent insights into the genetic basis of systemic lupus erythematosus. Ann Rheum Dis 2013; 72 Suppl 2:ii56.
3. Graham RR, Hom G, Ortmann W, Behrens TW. Review of recent genome-wide association scans in lupus. J Intern Med 2009; 265:680.
4. Boackle SA. Advances in lupus genetics. Curr Opin Rheumatol 2013; 25:561.