{"doi":"10.1016/j.jcmgh.2024.02.010","title":"Genetic Variation Between Small Bowel and Colon-Predominant Crohn's Disease","abstract":"The genomic contribution to inflammatory bowel diseases (IBDs) is complex and polygenic,1Serra E.G. et al.Nat Commun. 2020; 11: 995Crossref PubMed Scopus (0) Google Scholar with more than 240 susceptibility loci identified by genome-wide association studies.2Cordero R.Y. et al.Hum Mol Genet. 2023; 32: 873-882Crossref PubMed Scopus (0) Google Scholar Although genome-wide association studies are powerful, those still carry limitations, and commonly are not powered toward rare subtype analysis within a disease group.3Tam V. et al.Nat Rev Genet. 2019; 20: 467-484Crossref PubMed Scopus (0) Google Scholar Therefore, in this study, we set out to compare the genetics (exomes) of patients with proximal small-bowel–predominant Crohn’s disease (SB-CD) (L4) or colon-predominant Crohn’s disease (C-CD) (L2 and/or colon-predominant L3). We also examined a differentiating candidate gene in a mouse model of colitis to address the translational relevance of our findings. Susceptibility subject–gene bipartite networks in SB-CD and C-CD also were generated to study the polygenic background of the disease subtypes. Eight SB-CD and 11 C-CD cases met inclusion criteria. The clinical characteristics of these patients are included in Table 1. With methods described in the Supplemental Materials, we identified 115 single-nucleotide polymorphisms (SNPs) with a combined annotation-dependent depletion (CADD) (a tool for scoring the deleteriousness of single-nucleotide variants) PHRED score >10 associated with 97 genes, which had significantly (P < .01) different allele variation between C-CD and SB-CD. An SNP in the EFNA3 gene was among the top 28 candidates with a CADD score >20 to differentiate between the 2 phenotypically distinct CD groups (Supplementary Table 1). EFNA3 rs17723260 (predicted to be deleterious) was found to have a significantly lower allele frequency (4.5%) in C-CD, compared with its allele frequency of 37.5% in SB-CD (chi square P = .0097). This finding indicated that EFNA3 might play a role in modulating colonic inflammation, in which a deleterious genetic defect might provide protection against colitis (and direct autoimmunity against the proximal small bowel) in the polygenic background of CD. Importantly, EFNA3 has been linked to ulcerative colitis4Fenton C.G. et al.Inflamm Bowel Dis. 2021; 27: 94-105Crossref PubMed Scopus (0) Google Scholar and CD5Ventham N.T. et al.Cell Mol Gastroenterol Hepatol. 2023; 16: 431-450Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar as well. The other 4 genes associated with the top 5 SNP candidates (Supplementary Table 1) already have been connected with IBD or mammalian intestinal inflammation. ACACB up-regulated in small-bowel strictures of the marmoset,6Sheh A. et al.Sci Rep. 2022; 12: 4430Crossref Scopus (8) Google Scholar STEAP1B linked to adult IBD,7Li Q. et al.Gastroenterology. 2016; 150: 1196-1207Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar DSG1as a serologic marker of complicated CD,8Yau Y.Y. et al.Mol Cell Proteomics. 2017; 16: 1244-1257Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and CYP4F2 in which the specific polymorphism identified in this study (rs2108622) also has been observed to associate significantly with CD by Costea et al.9Costea I. et al.PLoS One. 2010; 5e15672Crossref Scopus (22) Google ScholarTable 1Demographic and Baseline Characteristics of Patients With Either C-CD or SB-CDC-CD (n = 11)SB-CD (n = 8)P valueMean age at diagnosis, y10.911.95Sex, % female36.3251Ethnicity, % Caucasian72.787.5.6Paris location, % L1050.018 L254.50.018 L345.525.63 L4a18.237.5.6 L4b0100.0001Paris behavior, % B145.512.5.177 B227.262.5.18 B318.20.485 B2B39.125.546Perianal disease, % yes36.412.5.338Presence of granulomas, % yes33.3 (2/6)33.3 (3/9)1Surgical intervention required, % yes54.575.633Surgery in first 2 years, % yes33.3 (2/6)50 (3/6)1Type of surgery, %n = 6n = 6 Partial colectomy50501 Total colectomy33.30.455 Ileocecotomy016.71 Ente","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2024,"id":479622,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9484,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":63735,"name":"R. Alan Harris","orcid":"0000-0002-7333-4752","position":1,"is_corresponding":false},{"id":1318715,"name":"Justin H. Qian","orcid":"0000-0001-6982-0849","position":2,"is_corresponding":false},{"id":489890,"name":"Numan Oezguen","orcid":"0000-0002-3175-2382","position":3,"is_corresponding":false},{"id":1278261,"name":"Ashleigh Watson","orcid":"0000-0001-6272-466X","position":4,"is_corresponding":false},{"id":1318716,"name":"Réka Szigeti","orcid":"0000-0002-8650-1265","position":5,"is_corresponding":false},{"id":1058940,"name":"Stanley Cho","orcid":null,"position":6,"is_corresponding":false},{"id":398114,"name":"Wenly Ruan","orcid":"0000-0002-0391-5543","position":7,"is_corresponding":false},{"id":1319059,"name":"Savini Britto","orcid":null,"position":8,"is_corresponding":false},{"id":274066,"name":"Antone R. Opekun","orcid":"0000-0003-4837-6480","position":9,"is_corresponding":false},{"id":269707,"name":"Geoffrey A. Preidis","orcid":"0000-0002-2206-6452","position":10,"is_corresponding":false},{"id":486456,"name":"Richárd Kellermayer","orcid":"0000-0002-4146-1335","position":11,"is_corresponding":false},{"id":953584,"name":"Halee Patel","orcid":null,"position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:06:54.284166Z","pmid":"38369131","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}