The presence and magnitude of immune responses to microbial antigens are significantly associated with more aggressive disease phenotypes among children with CD. This is the first study to prospectively demonstrate that the time to develop a disease complication in children is significantly faster in the presence of immune reactivity, thereby predicting disease progression to more aggressive disease phenotypes among pediatric CD patients.

Background-The IL-23 receptor (IL-23R) has been found to be associated with small bowel Crohn's disease (CD) in a whole genome association study. Specifically, the rare allele of the R381Q single nucleotide polymorphism (SNP) conferred protection against CD. It is unknown whether IL-23R is associated with IBD in children. The aim was to examine the association of IL-23R with susceptibility to IBD in pediatric patients.

Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.

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Objective Genome-wide association studies (GWAS) have identified multiple Crohn’s disease (CD) susceptibility loci, including association with non-coding intergenic single nucleotide polymorphisms (SNPs) at 10q21. Design To fine-map the 10q21 locus, we genotyped 86 SNPs in 1632 CD cases and 961 controls and performed single marker and conditional analyses using logistic regression. Results We observed association with CD risk spanning eleven SNPs (p< 0.001). The most significant association observed was at the nonsynonymous SNP rs7076156 (Ala62Thr) in ZNF365. The alanine allele was over-represented in CD (p= 5.23×10−7; OR= 1.39 [1.22–1.58]); allele frequency 76% CD, 69.7% controls). Conditional analysis on rs7076156 nullified all other significant associations, suggesting that this is the causative variant at this locus. Four isoforms of ZNF365 have previously been identified and rs7076156 is located in an exon unique to ZNF365 isoform D. We demonstrated, using RT-PCR, expression of ZNF365D in intestinal resections from both CD subjects and controls. We identified markedly reduced ZNF365D mean expression levels in EBV-transformed lymphoblastoid cell lines (ELCLs) from CD subjects homozygous for the risk allele (Ala). A whole-genome microarray expression study further suggested that the Ala62Thr change in ZNF365 isoform D is related to differential expression of the genes ARL4A, MKKS, RRAGD, SUMF2, TDR1 and ZNF148 in CD. Conclusions Collectively our data support the hypothesis that the nonsynonymous Ala62Thr SNP rs7076156 underlies the association between 10q21 and CD risk and suggests that this SNP acts by altering expression of genes under the control of ZNF365 isoform D.