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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 volume 31, pages 1440–1446 (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.

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Data availability

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

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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 31, 1440–1446 (2023). https://doi.org/10.1038/s41431-023-01298-9

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