Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population

Abstract

Most inflammatory bowel diseases (IBDs) are classic complex disorders represented by common alleles. Here we aimed to define the genetic architecture of pediatric and adult-onset IBDs for the Polish population. A total of 1495 patients were recruited, including 761 patients with Crohn’s disease (CD; 424 pediatric), 734 patients with ulcerative colitis (UC; 390 pediatric), and 934 healthy controls. Allelotyping employed a pooled-DNA genome-wide association study (GWAS) and was validated by individual genotyping. Whole exome sequencing (WES) was performed on 44 IBD patients diagnosed before 6 years of age, 45 patients diagnosed after 40 years of age, and 18 healthy controls. Altogether, out of 88 selected SNPs, 31 SNPs were replicated for association with IBD. A novel BRD2 (rs1049526) association reached significance of P = 5.2 × 10−11 and odds ratio (OR) = 2.43. Twenty SNPs were shared between pediatric and adult patients; 1 and 7 were unique to adult-onset and pediatric-onset IBD, respectively. WES identified numerous rare and potentially deleterious variants in IBD-associated or innate immunity-associated genes. Deleterious alleles in both groups were over-represented among rare variants in affected children. Our GWAS revealed differences in the polygenic architecture of pediatric- and adult-onset IBD. A significant accumulation of rare and deleterious variants in affected children suggests a contribution by yet unexplained genetic components.

Colonic Epithelial miR-31 Associates with the Development of Crohn’s Phenotypes

“…Genetic variants in NOD2, MHC, and MST1 3p21 were shown to be associated with disease location (colonic CD, ileal CD and ulcerative colitis (UC)) but not disease behavior (3). But, the genetic contribution to CD pathogenesis has been shown to be disproportionate, ranging from most impactful in very early onset IBD (26) (VEOIBD) to modest significance in older pediatric and adult IBD patients (27)(28)(29)(30). In rectal tissue from pediatric patients, expression patterns of IL-13, IL23A, and IL17 distinguished colonic CD from UC (31).…”

Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte–Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn’s Disease

“…We conducted the largest pediatric IBD WES study to date and identified 18 potentially damaging heterozygous or homozygous missense mutations in CSF2RA or CSF2RB. 20 Only 1 of these mutations, CSF2RA A17G, was present at a high enough frequency to test for an association with the neutrophil GMSI in primary patient-derived cells. We confirmed that CSF2RA A17G carriage was associated with a 2-fold reduction in the neutrophil GMSI.…”

“…A significant effect on the GM-CSF-induced STAT5 stimulation index was defined as a reduction in the mean (SD) from 100 (40) in disease controls lacking a specific genetic variant to 60 (20) in cases carrying a specific genetic variant. Ten subjects carrying the variant of interest, compared with 10 subjects not carrying the variant, were sufficient to test for this difference with >80% power and an α of 0.05.…”

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

“…The percentage of patients with genetically diagnosed VEO‐IBD varies between centers and cohorts and ranges from 5%‐31% depending the composition of the cohort . The reasons behind the missing heritability are multifactorial.…”

“…The percentage of patients with genetically diagnosed VEO-IBD varies between centers and cohorts and ranges from 5%-31% depending the composition of the cohort. [211][212][213][214][215][216] conservation-based tools like Genomic Evolutionary Rate Profiling (GEPR), 228 and integrative methods such as Combined Annotation Dependent Depletion (CADD). 229 These tools aim to decipher the consequence of genetic variants on protein structure and function.…”