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  • Li, DalinF. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, USA (author)

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition

  • Article/chapterEnglish2016

Publisher, publication year, extent ...

  • Saunders Elsevier,2016
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:oru-52738
  • https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-52738URI
  • https://doi.org/10.1053/j.gastro.2016.06.051DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:134761776URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Funding Agencies:National Institutes of Health U01DK062413  U01DK062420  U01DK062422  U01DK062429  U01DK062423  U01DK062431  U01DK062432  F30DK098927  P01DK046763  P30CA016042  R01CA141743  R01DK087694  R01DK092235  R01DK098231  R01HS021747  T32DK007180  T32GM007205  U01AI067068  U54DE023798  UL1TR000124Crohn's and Colitis Foundation of AmericaDeutsche Forschungsgemeinschaft DFG BR 1912/6-1  Ni575/7-1  Ni 575/4-1Else Kroner-Fresenius-Stiftung (Else Kroner Exzellenzstipendium) 2010_EKES.32Inflammatory Bowel Disease Genetic Research Chair at the University of PittsburghChildren's Hospital of PhiladelphiaÖrebro University Hospital Research FoundationRoyal Brisbane and Women's Hospital Research FoundationSanford J Grossman Charitable TrustSUCCESSSwiss National Science Foundation 146290Eli and Edythe Broad Foundation IBD-0164REuropean UnionKenneth Rainin Chair for Inflammatory Bowel Disease ResearchLeona M and Harry B Helmsley Charitable TrustNational Health and Medical Research Council APP498405
  • Background & Aims: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA).Methods: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing.Results: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)).Conclusions: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

Subject headings and genre

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  • Achkar, Jean-PaulDepartment of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland OH, USA (author)
  • Haritunians, TalinF. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, USA (author)
  • Jacobs, Jonathan P.Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA (author)
  • Hui, Ken Y.Division of Gastroenterology, Department of Medicine, Yale University, New Haven CT, USA (author)
  • D'Amato, MauroKarolinska Institutet (author)
  • Brand, StephanDepartment of Medicine II, University Hospital Munich-Grosshadern, Munich, Germany (author)
  • Radford-Smith, GrahamInflammatory Bowel Diseases, Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia; Department of Gastroenterology, Royal Brisbane and Women’s Hospital, Brisbane, Australia; School of Medicine, University of Queensland, Brisbane, Australia (author)
  • Halfvarson, Jonas,1970-Örebro universitet,Institutionen för medicinska vetenskaper,Department of Gastroenterology, Örebro University Hospital, Örebro, Sweden(Swepub:oru)jshn (author)
  • Niess, Jan-HendrikDepartment of Internal Medicine I, University of Ulm, Ulm, Germany; Division of Visceral Surgery and Medicine, Department of Gastroenterology, Inselspital Bern, Bern, Switzerland; Gastroenterology and Hepatology, University Hospital, Basel, Switzerland (author)
  • Kugathasan, SubraDepartment of Pediatrics, Emory University School of Medicine and Children's Health Care of Atlanta, Atlanta Ga, USA (author)
  • Büning, CarstenInternal Medicine, Krankenhaus Waldfriede, Berlin, Germany (author)
  • Schumm, L. PhilipDepartment of Public Health Sciences, Biostatistical Laboratory, University of Chicago, Chicago ILL, USA (author)
  • Klei, LambertusDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh PA, USA (author)
  • Ananthakrishnan, AshwinGastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA (author)
  • Aumais, GuyUniversité de Montréal, Montréal QC, Canada; Hopital Maisonneuve Rosemont, Montréal QC, Canada (author)
  • Baidoo, LeonardDivision of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh PA, USA (author)
  • Dubinsky, MarlaF. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York NY, USA (author)
  • Fiocchi, ClaudioPathobiology Department, Cleveland Clinic, Cleveland OH, USA (author)
  • Glas, JürgenDepartment of Preventive Dentistry and Periodontology, Ludwig-Maximilians-University, Munich, Germany (author)
  • Milgrom, RaquelZane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada (author)
  • Proctor, Deborah D.Division of Gastroenterology, Department of Medicine, Yale University, New Haven CT, USA (author)
  • Regueiro, MiguelDivision of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh PA, USA (author)
  • Simms, Lisa A.Inflammatory Bowel Diseases, Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia (author)
  • Stempak, Joanne M.Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto ON, Canada (author)
  • Targan, Stephan R.F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, USA (author)
  • Törkvist, LeifKarolinska Institutet (author)
  • Sharma, YashodaDepartment of Genetic & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York NY, USA (author)
  • Devlin, BernieDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh PA, USA (author)
  • Borneman, JamesDepartment of Plant Pathology and Microbiology, University of California, Riverside, Riverside CA, USA (author)
  • Hakonarson, HakonCenter for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia PA, USA (author)
  • Xavier, Ramnik J.Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston , USA; Broad Institute of MIT and Harvard, Cambridge MA, USA (author)
  • Daly, MarkBroad Institute of MIT and Harvard, Cambridge MA, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA (author)
  • Brant, Steven R.Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University, Baltimore MD, USA; Bloomberg School of Public Health, Johns Hopkins University, Baltimore MD, USA (author)
  • Rioux, John D.Université de Montréal, Montréal QC, Canada; Montreal Heart Institute, Montréal OC, Canada (author)
  • Silverberg, Mark S.Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto ON, Canada (author)
  • Cho, Judy H.Department of Genetic & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York NY, USA; Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York NY, USA (author)
  • Braun, JonathanPathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles CA, USA; (author)
  • McGovern, Dermot P. B.F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, USA (author)
  • Duerr, Richard H.Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh PA, USA (author)
  • F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, USADepartment of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland OH, USA (creator_code:org_t)

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  • In:Gastroenterology: Saunders Elsevier151:4, s. 724-7320016-50851528-0012

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