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A family with ulcerative colitis maps to 7p21.1 and comprises a region with regulatory activity for the aryl hydrocarbon receptor gene

European Journal of Human Genetics (2023)Cite this article

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Abstract

We have mapped a locus on chromosome 7p22.3-7p15.3 spanning a 22.4 Mb region for ulcerative colitis (UC) by whole genome linkage analyses of a large Danish family. The family represent three generations with UC segregating as an autosomal dominant trait with variable expressivity. The whole-genome scan resulted in a logarithm of odds score (LOD score) of Z = 3.31, and a whole genome sequencing (WGS) of two affected excluded disease-causing mutations in the protein coding genes. Two rare heterozygote variants, rs182281985:G>A and rs541426369:G>A, both with low allele frequencies (MAF A:0.0001, gnomAD ver3.1.2), were found in clusters of ChiP-seq transcription factors binding sites close to the AHR (aryl hydrocarbon receptor) gene and the UC associated SNP rs1077773:G>A. Testing the two SNPs in a promoter reporter assay for regulatory activity revealed that rs182281985:G>A influenced the AHR promoter. These results suggest a regulatory region that include rs182281985:G>A close to the UC GWAS SNP rs1077773:G>A and further demonstrate evidence that the AHR gene on the 7p-tel region is a candidate susceptible gene for UC.

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Fig. 1: The pedigree of the large Danish family and plot of the chromosome 7 LOD scores.
Fig. 2: Schematic presentation of vector constructs uses for the AHR promoter assays and expression results.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Sairenji T, Collins KL, Evans DV. An update on inflammatory bowel disease. Prim Care. 2017;44:673–92. https://doi.org/10.1016/j.pop.2017.07.010.

    Article  Google Scholar 

  2. Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn’s disease. Lancet. 2017;389:1741–55. https://doi.org/10.1016/S0140-6736(16)31711-1.

    Article  Google Scholar 

  3. Ungaro R, Mehandru S, Allen PB, Peyrin L, Colombel J-F. Ulcerative colitis. Lancet. 2017;389:1756–70. https://doi.org/10.1016/S0140-6736(16)32126-2.

    Article  Google Scholar 

  4. Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390:2769–78. https://doi.org/10.1016/S0140-6736(17)32448-0.

    Article  Google Scholar 

  5. Ellinghaus D, Bethune J, Petersen BS, Franke A. The genetics of Crohn’s disease and ulcerative colitis-status quo and beyond. Scand J Gastroenterol. 2014;50:13–23. https://doi.org/10.3109/00365521.2014.990507.

    Article  CAS  Google Scholar 

  6. Bager P, Gørtz S, Feenstra B, Andersen NN, Jess T, Frisch M, et al. Increased risk of inflammatory bowel disease in families with tonsillectomy: a Danish national cohort study. Epidemiology. 2019;30:256–62. https://doi.org/10.1097/EDE.0000000000000946.

    Article  Google Scholar 

  7. Santos MPC, Gomes C, Torres J. Familial and ethnic risk in inflammatory bowel disease. Ann Gastroenterol. 2018;31:14–23. https://doi.org/10.20524/aog.2017.0208.

    Article  Google Scholar 

  8. Younis N, Zarif R, Mahfouz R. Inflammatory bowel disease: between genetics and microbiota. Mol Biol Rep. 2020;47:3053–63. https://doi.org/10.1007/s11033-020-05318-5.

    Article  CAS  Google Scholar 

  9. Orholm M, Munkholm P, Langholz E, Nielsen OH, Sørensen TIA, Binder V. Familial occurrence of inflammatory bowel disease. N. Engl J Med. 1991;324:84–88. https://doi.org/10.1056/NEJM199101103240203.

    Article  CAS  Google Scholar 

  10. Brant SR. Update on the heritability of inflammatory bowel disease: the importance of twin studies. Inflamm Bowel Dis. 2011;17:1–5. https://doi.org/10.1002/ibd.21385.

    Article  Google Scholar 

  11. Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47:979–86. https://doi.org/10.1038/ng.3359.

    Article  CAS  Google Scholar 

  12. Ellinghaus D, Jostins L, Spain SL, Cortes A, Bethune J, Han H, et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet. 2016;48:510–8. https://doi.org/10.1038/ng.3528.

    Article  CAS  Google Scholar 

  13. de Lange KM, Moutsianas L, Lee JC, Lamb CA, Luo Y, Kennedy NA, et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet. 2017;49:256–61. https://doi.org/10.1038/ng.3760.

    Article  CAS  Google Scholar 

  14. Huang H, Fang M, Jostins L, Mirkov MU, Boucher G, Anderson CA, et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature. 2017;547:173–8. https://doi.org/10.1038/nature22969.

    Article  CAS  Google Scholar 

  15. Mirkov MU, Verstockt B, Cleynen I. Genetics of inflammatory bowel disease: beyond NOD2. Lancet Gastroenterol Hepatol. 2017;2:224–34. https://doi.org/10.1016/S2468-1253(16)30111-X.

    Article  Google Scholar 

  16. Corbaz A, ten Hove T, Herren S, Graber P, Schwartsburd B, Belzer I, et al. IL-18-binding protein expression by endothelial cells and macrophages is up-regulated during active Crohn’s disease. J Immunol. 2002;168:3608–16. https://doi.org/10.4049/jimmunol.168.7.3608.

    Article  CAS  Google Scholar 

  17. Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest. 2004;113:1490–7. https://doi.org/10.1172/JCI19836.

    Article  CAS  Google Scholar 

  18. van Heel DA, Fisher SA, Kirby A, Daly MJ, Rioux JD, Lewis CM. Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs. Hum Mol Genet. 2004;13:763–70. https://doi.org/10.1093/hmg/ddh090.

    Article  CAS  Google Scholar 

  19. Franke A, McGovern DPB, Barrett JC, Wang K, Radford-Smith GLAhmad T, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42:1118–25. https://doi.org/10.1038/ng.717.

    Article  CAS  Google Scholar 

  20. Yoneno K, Hisamatsu T, Shimamura K, Kamada N, Ichikawa R, Kitazume MT, et al. TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn’s disease. Immunology. 2013;139:19–29. https://doi.org/10.1111/imm.12045.

    Article  CAS  Google Scholar 

  21. de Lange KM, Barrett JC. Understanding inflammatory bowel disease via immunogenetics. J Autoimmun. 2015;64:91–100. https://doi.org/10.1016/j.jaut.2015.07.013.

    Article  CAS  Google Scholar 

  22. Eiberg H, Nielsen LS, Klausen J, Dahlén M, Kristensen M, Bisgaard M, et al. Linkage between serum cholinesterase 2 (CHE2) and ▯‑crystalline gene cluster (CRYG): assignment to chromosome 2. Clin Genet. 1989;35:313–321. https://doi.org/10.1111/j.1399-0004.1989.tb02951.x.

    Article  CAS  Google Scholar 

  23. Ott J. A computer program for linkage analysis of general human pedigrees. Am J Hum Genet. 1976;28:528–9.

    CAS  Google Scholar 

  24. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60. https://doi.org/10.1093/bioinformatics/btp324.

    Article  CAS  Google Scholar 

  25. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43:491–8. https://doi.org/10.1038/ng.806.

    Article  CAS  Google Scholar 

  26. Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics. 2015;31:2745–7. https://doi.org/10.1093/bioinformatics/btv195.

    Article  CAS  Google Scholar 

  27. Fishilevich S, Nudel R, Rappaport N, Hadar R, Plaschkes I, Stein TI, et al. GeneHancer: genome-wide integration of enhancers and target genes in GeneCards, Database. 2017. https://doi.org/10.1093/database/bax028.

  28. Sloan CA, Chan ET, Davidson JM, Malladi VS, Strattan JS, Hitz BC, et al. ENCODE data at the ENCODE portal. Nucleic Acids Res. 2016;44(D1):D726–32. https://doi.org/10.1093/nar/gkv1160.

    Article  CAS  Google Scholar 

  29. Lee BT, Barber GP, Benet-Pagès A, Casper J, Clawson H, Diekhans M, et al. The UCSC Genome Browser database: 2022 update. Nucleic Acids Res. 2022;50(D1):D1115–D1122. https://doi.org/10.1093/nar/gkab959.

    Article  CAS  Google Scholar 

  30. Raman M, Martin K. One solution for cloning and mutagenesis: In-Fusion® HD Cloning Plus. Nat Methods. 2014;11:iii–v. https://doi.org/10.1038/nmeth.f.373.

    Article  CAS  Google Scholar 

  31. Dahlgaard K, Troelsen JT. Identification and functional analysis of gene regulatory sequences interacting with colorectal tumor suppressors. Methods Mol Biol. 2018;1765:57–77. https://doi.org/10.1007/978-1-4939-7765-9_4.

    Article  CAS  Google Scholar 

  32. Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43:246–52. https://doi.org/10.1038/ng.764.

    Article  CAS  Google Scholar 

  33. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012;491:119–24. https://doi.org/10.1038/nature11582.

    Article  CAS  Google Scholar 

  34. Haritunians T, Taylor KD, Targan SR, Dubinsky M, Ippoliti A, Kwon S, et al. Genetic predictors of medically refractory ulcerative colitis. Inflamm Bowel Dis. 2010;16:1830–40. https://doi.org/10.1002/ibd.21293.

    Article  Google Scholar 

  35. Burke KE, Khalili H, Garber JJ, Haritunians T, McGovern DPB, Xavier RJ, et al. Genetic markers predict primary nonresponse and durable response to anti-tumor necrosis factor therapy in ulcerative colitis. Inflamm Bowel Dis. 2018;24:1840–8. https://doi.org/10.1093/ibd/izy083.

    Article  Google Scholar 

  36. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474:307–17. https://doi.org/10.1038/nature10209.

    Article  CAS  Google Scholar 

  37. Mathew CG, Lewis CM. Genetics of inflammatory bowel disease: progress and prospects. Hum Mol Genet. 2004;13:R161–8. https://doi.org/10.1093/hmg/ddh079.

    Article  CAS  Google Scholar 

  38. Hugot J-P, Laurent-Puig P, Gower-Rousseau C, Olson JM, Lee JC, Beaugerie L, et al. Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Nature. 1996;379:821–3. https://doi.org/10.1038/379821a0.

    Article  CAS  Google Scholar 

  39. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard J-P, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599–603. https://doi.org/10.1038/35079107.

    Article  CAS  Google Scholar 

  40. Ogura Y, Bonen D, Inohara N, Nicolae D. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001;411:603–6. https://doi.org/10.1038/35079114.

    Article  CAS  Google Scholar 

  41. Hampe J, Frenzel H, Mirza MM, Croucher PJP, Cuthbert A, Mascheretti S, et al. Evidence for a NOD2-independent susceptibility locus for inflammatory bowel disease on chromosome 16p. Proc Natl Acad Sci USA. 2002;99:321–6. https://doi.org/10.1073/pnas.261567999.

    Article  CAS  Google Scholar 

  42. Negroni A, Pierdomenico M, Cucchiara S, Stronati L. NOD2 and inflammation: current insights. J Inflamm Res. 2018;11:49–60. https://doi.org/10.2147/JIR.S137606.

    Article  CAS  Google Scholar 

  43. Philpott DJ, Sorbara MT, Robertson SJ, Croitoru K, Girardin SE. NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol. 2014;14:9–23. https://doi.org/10.1038/nri3565.

    Article  CAS  Google Scholar 

  44. Benson JM, Shepherd DM. Aryl hydrocarbon receptor activation by TCDD reduces inflammation associated with Crohn’s disease. Toxicol Sci. 2011;120:68–78. https://doi.org/10.1093/toxsci/kfq360.

    Article  CAS  Google Scholar 

  45. Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell. 2011;147:629–40. https://doi.org/10.1016/j.cell.2011.09.025.

    Article  CAS  Google Scholar 

  46. Lamas B, Natividad JM, Sokol H. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol. 2018;11:1024–38. https://doi.org/10.1038/s41385-018-0019-2.

    Article  CAS  Google Scholar 

  47. Mizoguchi A, Yano A, Himuro H, Ezaki Y, Sadanaga T, Mizoguchi E. Clinical importance of IL-22 cascade in IBD. J Gastroenterol. 2018;53:465–74. https://doi.org/10.1007/s00535-017-1401-7.

    Article  CAS  Google Scholar 

  48. Sugimoto S, Naganuma M, Kiyohara H, Arai M, Ono K, Mori K, et al. Clinical efficacy and safety of oral Qing-Dai in patients with ulcerative colitis: a single-center open-label prospective study. Digestion. 2016;93:193–201. https://doi.org/10.1159/000444217.

    Article  CAS  Google Scholar 

  49. Metidji A, Omenetti S, Crotta S, Li Y, Nye E, Ross E, et al. The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity. 2018;49:353–62.e5. https://doi.org/10.1016/j.immuni.2018.07.010.

    Article  CAS  Google Scholar 

  50. Cannon AS, Nagarkatti PS, Nagarkatti M. Targeting AhR as a novel therapeutic modality against inflammatory diseases. Int J Mol Sci. 2022;23:288. https://doi.org/10.3390/ijms23010288.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all family members for their participation in this study and Annemette Friis Mikkelsen and Marianne Lauridsen is thanked for excellent technical assistance and Rigshospitalets Microarray Center for the genotyping. HE was supported by the Danish Medical Research Council (22-02-0208), CBB by the Innovation Fund Denmark (0603-00320B), JTT and JBO received funding from Region Zealand and Roskilde University.

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Author notes

  1. These authors contributed equally: Hans Eiberg, Josephine B. Olsson.

Authors and Affiliations

  1. RCLINK, Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark

    Hans Eiberg

  2. Department of Science and Environment, Roskilde University, Roskilde, Denmark

    Josephine B. Olsson & Jesper T. Troelsen

  3. Department of Clinical Immunology, Zealand University Hospital, Naestved, Denmark

    Josephine B. Olsson

  4. Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Mads Bak

  5. Research Group for Microbial Biotechnology and Biorefining, National Food Institute, Technical University of Denmark, Kemitorvet building 202, 2800 Kgs, Lyngby, Denmark

    Claus Heiner Bang-Berthelsen

  6. Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark

    Lars Hansen

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Contributions

All authors have contributed to and approved the final manuscript and agreed to the order in which their names are listed. Hans Eiberg: Conceptualization and design of the study, linkage analysis, WGS data analysis and revising the manuscript. Josephine B Olsson: Construction of expression plasmids, cell transfection, promoter analysis and revising the manuscript. Mads Bak: WGS, alignment, and analyses of data. Claus H Bang-Berthelsen: data analysis and associations data. Jesper T Troelsen: Design of promoter analysis, interpretation of data and revising the manuscript. Lars Hansen: Design of the study, data analysis, drafting and writing the manuscript.

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Correspondence to Hans Eiberg.

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The study protocols adhered to the tenets of the Declaration of Helsinki and the ARVO statement on human subjects and approved by the Danish National Committee on Health Research Ethics in 2019 (H-19019167).

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Eiberg, H., Olsson, J.B., Bak, M. et al. A family with ulcerative colitis maps to 7p21.1 and comprises a region with regulatory activity for the aryl hydrocarbon receptor gene. Eur J Hum Genet (2023). https://doi.org/10.1038/s41431-023-01298-9

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