GENETIC POLYMOPRHISMS MAY DIFFERENTIATE BETWEEN COMPLICATED PEDIATRIC SMALL BOWEL VERSUS COLONIC CROHN’S DISEASE

Abstract Objectives About 9% of pediatric Crohn’s disease (CD) patients experience complications within 3 years from diagnosis in spite of anti-Tumor Necrosis Factor-alpha (anti-TNF) biologic treatment. Within 5 years, such complications may require surgical interventions in up to 20% of cases. Due to the relatively rare nature of these complicated pediatric CD cases within large CD cohorts, traditional genome wide association studies (GWAS) rarely capture this patient population. Our aim was to identify critical genetic associations of anti-TNF refractory complicated pediatric CD subtypes. Methods The study was approved by BCM IRB. Included patients had developed CD between the ages of 6 and 18. The Paris classification was used to place patients in the following categories: 1. Anti-TNF refractory small bowel CD (RSB-CD): L4b; L4b/B2; or L4b/B2B3 who had or were imminent to have small bowel resection. 2.. Anti-TNF refractory colonic CD (RC-CD): L2 requiring ileal diversion; or L2/B2; or L2/B2B3 who had or were considered to receive colectomy or partial colonic resection. Whole-exome sequencing (WES) was performed from peripheral blood derived DNA. PLINK (https://www.cog-genomics.org/plink2/) was used to identify enriched single nucleotide polymorphisms (SNPs). The level of significance for exome wide differentiation was relaxed to p<0.01. The potential deleteriousness of single nucleotide variants was determined by CADD (https://cadd.gs.washington.edu/). Gene Ontology enRIchment anaLysis and visuaLizAtion tool (GORILLA) was used to compare gene lists associated with colonic enriched SNPs versus ileal enriched SNPs (http://geneontology.org/). Results In eight RSB-CD and 11 RC-CD cases, age at presentation, gender, ethnicity, and need for surgery (75% and 55%, respectively) did not significantly differ between the groups. There were 269 genes associated with 277 SNPs that had significantly (p<0.01) different allele variation between colonic vs ileal CD. Of these, 170 genes associated with 116 distinct SNPs had a CADD score of >10. Out of the top five SNP candidate associated genes, four (4/5 = 80%: EFNA3, STEAP1B, DSG1, and CYP4F2) have been already linked with Crohn’s disease and/or colitis. GORILLA based investigation indicated that colonic CD associated genes were enriched (p<0.001) in biologic function relevant for lipid metabolic process (GO:0006629), small molecule metabolic process (GO:0044281), and organic substance metabolic process (GO:0071704) compared to ileal CD associated genes. Conclusions We have uncovered candidate genetic risk loci, which may differentially influence pediatric CD towards developing primarily small intestinal or colonic complications. The discovered loci hold significant potential as novel genetic modifiers, which may set the basis for risk assessment, prevention and personalized treatment against complicated pediatric CD.