Abstract
BackgroundRecent GWAs and meta-analyses have outlined about 100 susceptibility genes/loci for inflammatory bowel diseases (IBD). In this study we aimed to investigate the influence of SNPs tagging the genes/loci PTGER4, TNFSF15, NKX2-3, ZNF365, IFNG, PTPN2, PSMG1, and HLA in a large pediatric- and adult-onset IBD Italian cohort.MethodsEight SNPs were assessed in 1,070 Crohn's disease (CD), 1,213 ulcerative colitis (UC), 557 of whom being diagnosed at the age of ≤16 years, and 789 healthy controls. Correlations with sub-phenotypes and major variants of NOD2 gene were investigated.ResultsThe SNPs tagging the TNFSF15, NKX2-3, ZNF365, and PTPN2 genes were associated with CD (P values ranging from 0.037 to 7×10−6). The SNPs tagging the PTGER4, NKX2-3, ZNF365, IFNG, PSMG1, and HLA area were associated with UC (P values 0.047 to 4×10−5). In the pediatric cohort the associations of TNFSF15, NKX2-3 with CD, and PTGER4, NKX2-3, ZNF365, IFNG, PSMG1 with UC, were confirmed. Association with TNFSF15 and pediatric UC was also reported. A correlation with NKX2-3 and need for surgery (P = 0.038), and with HLA and steroid-responsiveness (P = 0.024) in UC patients was observed. Moreover, significant association in our CD cohort with TNFSF15 SNP and colonic involvement (P = 0.021), and with ZNF365 and ileal location (P = 0.024) was demonstrated.ConclusionsWe confirmed in a large Italian cohort the associations with CD and UC of newly identified genes, both in adult and pediatric cohort of patients, with some influence on sub-phenotypes.
Highlights
The pathogenesis of inflammatory bowel diseases (IBD), namely Crohn’s disease (CD) and ulcerative colitis (UC), is still incompletely understood, but it is widely accepted that the two conditions result from an inappropriate and exaggerated mucosal immune response to constituents of the intestinal flora in a genetically susceptible host [1,2]
Genome-wide association (GWA) studies have identified several genes involved in the pathogenesis of IBD and, subsequently GWAS meta-analysis has led to confirmation of more than 70 genes or loci that confer susceptibility to CD and 47 to UC, mostly in adult populations [3,4,5]
A subsequent North American genome-wide association (GWA) study identified two additional loci for UC located on chromosome 1p36 and 12q15, each of them harboring multiple genes, including several with a definite role in inflammation and immunity, like group II secreted phospholipase A2 (PLA2G2E), interferon gamma (IFNG), interleukin 26 (IL26) and interleukin 22 (IL22)
Summary
The pathogenesis of inflammatory bowel diseases (IBD), namely Crohn’s disease (CD) and ulcerative colitis (UC), is still incompletely understood, but it is widely accepted that the two conditions result from an inappropriate and exaggerated mucosal immune response to constituents of the intestinal flora in a genetically susceptible host [1,2]. Genome-wide association (GWA) studies have identified several genes involved in the pathogenesis of IBD and, subsequently GWAS meta-analysis has led to confirmation of more than 70 genes or loci that confer susceptibility to CD and 47 to UC, mostly in adult populations [3,4,5]. A GWA study carried out in pediatric-onset IBD patients identified two novel IBD loci located on chromosome 20q13 and 21q22, close to the tumor necrosis factor receptor superfamily member 6B (TNFRSF6B) and proteasome-assembling chaperone 1 (PSMG1) genes [10]. In this study we aimed to investigate the influence of SNPs tagging the genes/loci PTGER4, TNFSF15, NKX2-3, ZNF365, IFNG, PTPN2, PSMG1, and HLA in a large pediatric- and adult-onset IBD Italian cohort
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