Association of the T300A non-synonymous variant of the ATG16L1 gene with susceptibility to paediatric Crohn's disease

Abstract

increased to seven (5.6%) in group 1 and one (2.1%) in group 2 (p = 0.445) after applying the immunohistochemical staining for detection of Mallory hyaline bodies. Pericellular fibrosis was identified in all steatohepatitis sections, but neutrophil inflammatory reaction was only identified in three specimens. Necroinflammatory injury, as reflected by modified Histology Activity Index (HAI), was significantly higher in group 1 than in group 2 (6.7 (2.7) vs 4.8 (3.4), p = 0.01). The fibrosis score was significantly higher in group 1 than in group 2 (3.3 (1.9) vs 1.8 (1.7), p = 0.002). Overweight/obesity (>25 kg/m 2) was reported in 80.6% of patients in group 1 and 62.5% in group 2 (p = 0.097), type 2 diabetes mellitus (fasting blood sugar .126 mg/dl and postprandial blood sugar 200 mg/dl on more than one occasion) was encountered in 27.4% of group 1 and 12.5% in group 2 (p = 0.038), while hypertriglyceridaemia (.200 mg/dl) was found in 6.5% of group 1 and 8.3% of group 2 (p = 0.759, table 1). While steatosis was not associated with HCV (p = 0.555), it was significantly correlated with overweight/obesity (p = 0.001), diabetes mellitus (p = 0.001) and hypertriglyceridaemia (p = 0.019). By multivariate analysis, only overweight/ obesity and diabetes mellitus were found to be significantly associated with steatosis. Neither necroinflammation nor fibrosis was correlated with steatosis in patients with HCV genotype 4 (p = 0.953 and 0.463). This lack of correlation may be explained by the discrepancy between a high frequency of steatosis (40%) and a low frequency of steatohepatitis (5.6%) in group 1. We conclude that hepatic steatosis is prevalent in nearly 40% of patients infected with HCV genotype 4, which is more highly attributed to associated metabolic factors. It seems that there is no correlation between necroinflammation or fibrosis and steatosis in patients with HCV genotype 4.

Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach

“…Interestingly, in a very recent study McCarroll et al 56 have shown that the causal variant responsible for IRGM Figure 1 Pooled data for the ATG16L1 rs2241880 susceptibility allele frequency (SAF). (a) Pooled data of Australian, 39 Belgian, 16 British, 14,21,23,25 Canadian, 31 Dutch, 28 German, 14,29,30 Italian, 27,33 Hungarian, 34 Japanese, 22 New Zealander, 26 North American 15,24 and Spanish cohorts for Crohn's disease (CD). (b) Pooled data of Australian, 39 British, 21,23,37 Canadian, 31 Dutch, 28 German, 14,29,30 Italian, 33 Hungarian, 34 New Zealander, 26,39 North American 15 and Spanish cohorts for ulcerative colitis (UC).…”

“…[14][15][16][21][22][23][24][25][26][27][28][29][30][31][32][33][34]38,39 Funnel plots and Egger tests were performed to analyse the publication bias of the meta-analysis. No statistically significant values were observed in CD studies (P ¼ 0.6) or UC studies (P ¼ 0.4), with symmetric funnel plots for both studies (Supplementary Figure 1).…”

“…[14][15][16] A large number of subsequent association studies have replicated the strong association of this gene with CD. [21][22][23][24][25][26][27][28][29][30][31][32][33][34] IRGM (immunity-related guanosine triphosphatase, the human homologue of mouse Irgm/Lrg47) encodes a GTP-binding protein that induces autophagy and plays an important role in innate immunity against intracellular pathogens. 35,36 Association of two immediately flanking IRGM gene polymorphisms (rs13361189 and rs4958847) with CD has recently been reported.…”

Definition of Phenotypic Characteristics of Childhood-Onset Inflammatory Bowel Disease

“…9 Gupta et al presented their findings in 600 pediatric CD patients at diagnosis: 61.5% of children had small bowel and colon involvement (compared with 50.5% in our study). Baldassano et al 17 recently described a small cohort of 142 children with CD: 86% had involvement of the small bowel and colon (Ϯ upper GI tract). Cucchiara et al 18 showed in an Italian cohort of pediatric CD patients with Ն1 year of follow-up (n ϭ 200) that 58% had ileocolonic CD (using the Vienna classification).…”

ATG16L1: A multifunctional susceptibility factor in Crohn disease

“…Numerous GWAS reports have identified several SNPs that regulate or communicate with the autophagic pathways and represent risk factors for Crohn disease. 7,[52][53][54][55][56][57][58] For instance, the SNPs in NOD2 are the most prominent risk-associated SNPs and can lead to early disease onset and a more complicated clinical course of Crohn disease, including fibrostenosis and fistulization. 11 These genetic variations also exhibit a marked reduction in bacterial autophagy due to the fact that NOD2 recruits ATG16L1 to the site of bacterial entry, 10 as described in more detail below.…”