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Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis

Abstract

Variants associated with meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10−12 at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10−9 at rs4077468) accounted for 5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.

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Figure 1: Meconium ileus GWAS identifies SNPs associated with genome-wide significance.
Figure 2: The apical membrane hypothesis identifies genes associated with meconium ileus.
Figure 3: Assessment of the nuclear envelope null hypothesis.

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Acknowledgements

The authors would like to thank the study particpiants, the Cystic Fibrosis Foundation (CFF) Patient Registry, the University of North Carolina DNA Laboratory and the Genome Quebec and McGill University Innovation Centre. We thank I. Wong for technical help with the replication genotyping, the computer specialists from the French study J.-F. Vibert and M. Mahloul and clinical research assistants Michon, A. Blondel and P. Touche involved in the study design and subject recruitment of the French sample, E. Hawbaker and A. Dang for data coordination in the Gene Modifier Study, Y. Berthiaume, A. Sandford and P. Pare for ascertainment of Canadian phenotype data and DNA, J. Breaton, M. Christofi, N. Anderson, K. Keenan, C. Taylor and J. Avolio for coordinating and verifying the Canadian data collection, E. Crowdy for database development and management in Canada, S. Norris, A. Kohl, P. Miller, L. Charnin, W. Hannah and S. Adams for recruitment, phenotyping and data entry at the University of North Carolina, W. Wolf for DNA analysis and H. Kelkar, T. Randall and A. Xu for bioinformatics at the University of North Carolina, and N. Wang, K. Kaniecki, J. Bonner and C. Watson for technical assistance at Johns Hopkins University. This work was supported in part by Genome Canada, through the Ontario Genomics Institute per research agreement 2004-OGI-3-05 (to P.R.D.), with the Ontario Research Fund, Research Excellence Program; the University of Toronto McLaughlin Centre (to L.S.); the Ontario Ministry of Research and Innovation Early Researcher award and the Natural Sciences and Engineering Research Council (to L.J.S.); Cystic Fibrosis Canada (CFC; to P.R.D., J.Z. and L.J.S.); the Natural Sciences and Engineering Research Council (NSERC; F250053-2008 to L.S.); the Canadian Institutes of Health Research (CIHR; MOP 84287 to L.S. and MOP 258916 to L.J.S.); the Lloyd Carr-Harris Foundation; the US National Institutes of Health (R01 HL68927 (G.R.C.), K23 DK083551 (S.M.B.), R01 HL068890 (M.R.K.), R01 DK066368 (M.R.K.), R01 HL095396 (M.R.K.) and HG-0004314 (L.J.S.)); the US CFF (CUTTIN06P0, R025-CR07, KNOWLE00A0, RDP-R026-CR07 and DRUMM0A00); the Flight Attendant Medical Research Institute (FAMRI2006 to G.R.C.); the Lawson Wilkins Pediatric Endocrine Society Clinical Scholar Award (to S.M.B.); INSERM; AP-HP; Université Pierre et Marie Curie Paris; Agence Nationale de la Recherche (R09186DS to H.C.), Direction Générale de la Santé; Association Vaincre la Mucoviscidose, Chancellerie des Universités (Legs Poix); Association Agir Informer Contre la Mucoviscidose; and Groupement d'Intérêt Scientifique (GIS)–Institut des Maladies Rares. Funds for genome-wide genotyping of North American participants were generously provided by the US CFF. R.D. received a Joint Fellowship from the CIHR and Ontario Women's Health Council. Contributing cystic fibrosis centers and principal investigators for the North American study collection: S. Aaron, Ottawa General Hospital, Ottawa, Ontario, Canada; F. Accurso, University of Colorado Health Sciences Center, Aurora, Colorado, USA; J. Acton, Cincinnati Children's Hospital and Medical Center, Cincinnati, Ohio, USA; R. Ahrens, University of Iowa Hospitals & Clinics, Iowa City, Iowa, USA; G. Aljadeff, Lutheran General Children's Hospital, Park Ridge, Illinois, USA; C. Allard, Hôpital de Chicoutimi, Chicoutimi, Quebec, Canada; R. Amaro, University of Texas at Tyler Health Center, Tyler, Texas, USA; R. Anbar, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA; P. Anderson, University of Arkansas, Little Rock, Arkansas, USA; A. Atlas, Morristown Memorial Hospital, Morristown, New Jersey, USA; S. Bell, The Prince Charles Hospital, Brisbane, Queensland, Australia; M. Berdella, St. Vincent's Hospital & Medical Center, New York, New York, USA; Y. Berthiaume, Hôtel Dieu De Montréal, Montreal, Quebec, Canada; J. Biller, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA; G. Bishop, Saint John Regional Hospital, Saint John, New Brunswick, Canada; C. Bjornson, Alberta Children's Hospital, Calgary, Alberta, Canada; H. Black, Asthma & Allergy Specialists, Charlotte, North Carolina, USA; P. Black, Children's Mercy Hospital, Kansas City, Missouri, USA; S. Boas, Children's Asthma Respiratory & Exercise Specialists, Glenview, Illinois, USA; M. Boland, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; D. Borowitz, Women & Children's Hospital of Buffalo, Buffalo, New York, USA; R. Boswell, University of Tennessee, Memphis, Tennessee, USA; J. Boucher, Centre Hospitalier Régional de Rimouski, Rimouski, Quebec, Canada; B. Bourke, Our Lady's Children Hospital, Dublin, Ireland; C.M. Bowman, Medical University of South Carolina, Charleston, South Carolina, USA; M. Boyle, Johns Hopkins Hospital, Baltimore, Maryland, USA; C. Brown, California Pacific Medical Center, San Francisco, California, USA; D. Brown, Pediatric Pulmonary Associates, Columbia, South Carolina, USA; N. Brown, University of Alberta Hospitals, Edmonton, Alberta, Canada; J. Brusky, University Hospital, Saskatoon, Saskatchewan, Canada; L.F. Caffey, University of New Mexico, Albuquerque, New Mexico, USA; A. Cantin, Centre Hospitalier Universitaire de Sherbrooke, Fleurimont, Sherbrooke, Quebec, Canada; R. Casciaro, Istituto Giannina Gaslini, Genoa, Italy; C. Castellani, Azienda Ospedaliera de Verona, Verona, Italy; B. Chatfield, University of Utah Health Sciences Center, Salt Lake City, Utah, USA; S. Chesrown, University of Florida, Gainesville, Florida, USA; M. Chilvers, British Columbia Children's Hospital, Vancouver, British Columbia, Canada; B. Chipps, Sutter Medical Center, Sacramento, California, USA; M. Cipolli, Azienda Ospedaliera de Verona, Verona, Italy; J.P. Clancy, University of Alabama at Birmingham, Birmingham, Alabama, USA; R. Cohen, Kaiser Permanente, Portland, Oregon, USA; J. Colombo, University of Nebraska Medical Center, Omaha, Nebraska; J. Cronin, Women & Children's Hospital of Buffalo, Buffalo, New York, USA; M. Cruz, St. Mary's Medical Center, West Palm Beach, Florida, USA; J. Cunningham, Cook Children's Medical Center, Fort Worth, Texas, USA; G. Davidson, British Columbia Children's Hospital, Vancouver, British Columbia, Canada; L. Davies, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA; D. Debray, Centre Hospitalier Universitaire de Bicêtre, Bicêtre, France; J. DeCelie-Germana, Schneider Children's Hospital, New Hyde Park, New York, USA; A. Devenny, Royal Hospital for Sick Children, Edinburgh, UK; E. DiMango, Columbia University Medical Center, New York, New York, USA; D. Doornbos, Via-Christi St. Francis, Wichita, Kansas, USA; A. Dozor, New York Medical College–Westchester Medical Center, Valhalla, New York, USA; J. Dunitz, University of Minnesota, Minneapolis, Minnesota, USA; M. Egan, Yale University School of Medicine, New Haven, Connecticut, USA; J. Eichner, Great Falls Clinic, Great Falls, Montana, USA; G. Elliot, Virginia Commonwealth University, Richmond, Virginia, USA; J. Farrell, Janeway Child Health Centre, St. John's, Newfoundland and Labrador, Canada; T. Ferkol, St. Louis Children's Hospital, Saint Louis, Missouri, USA; S. Fiel, Morristown Memorial Hospital, Morristown, New Jersey, USA; P. Flume, Medical University of South Carolina, Charleston, South Carolina, USA; A. Freitag, Chedoke-McMaster Hospital, Hamilton, Ontario, Canada; M. Franco, Miami Children's Hospital, Miami, Florida, USA; D. Froh, University of Virginia Health System, Charlottesville, Virginia, USA; N. Garey, Saint John Regional Hospital, Saint John, New Brunswick, Canada; D. Geller, Nemours Children's Clinic Orlando, Florida, USA; W. Gershan, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA; R. Gibson, Children's Hospital & Regional Medical Center, Seattle, Washington, USA; R. Giusti, Long Island College Hospital, Brooklyn, New York, USA; J. Gjevre, University Hospital, Saskatoon, Saskatchewan, Canada; M. Gondor, University of South Florida, Saint Petersburg, Florida, USA; G. Gong, Phoenix Children's Hospital, Phoenix, Arizona, USA; S. Goulet, Centre Hospitalier Régional de Rimouski, Rimouski, Quebec, Canada; M. Guill, Medical College of Georgia, Augusta, Georgia, USA; H. Gutierrez, University of Alabama at Birmingham, Birmingham, Alabama, USA; A. Hadeh, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA; K. Hardy, Children's Hospital, Oakland, California, USA; K. Henderson, Janeway Health and Rehabilitation Centre, St. John's, Newfoundland and Labrador, Canada; P. Hiatt, Texas Children's Hospital, Houston, Texas, USA; D. Hicks, Children's Hospital of Orange County, Orange, California, USA; B. Holmes, Regina General Hospital, Regina, Saskatchewan, Canada; D. Holsclaw, University of Pennsylvania, Philadelphia, Pennsylvania, USA; P. Holzwarth, St. Vincent Hospital, Green Bay, Wisconsin, USA; R. Honicky, Michigan State University, East Lansing, Michigan, USA; M. Howenstine, Riley Hospital for Children, Indianapolis, Indiana, USA; D. Hughes, IWK Health Centre, Halifax, Nova Scotia, Canada; M. Jackson, St. Mary's Hospital, Kitchener, Ontario, Canada; P. James, Lutheran Hospital, Fort Wayne, Indiana, USA; A. Jenneret, Hôtel Dieu de Montréal, Montreal, Quebec, Canada; P. Joseph, University of Cincinnati, Cincinnati, Ohio, USA; J. Kanga, University of Kentucky, Lexington, Kentucky, USA; M. Katz, Baylor College of Medicine, Houston, Texas, USA; S. Kent, Victoria General Hospital, Victoria, British Columbia, Canada; W. Kepron, Health Sciences Centre, Winnipeg, Manitoba, Canada; M. Knowles, University of North Carolina, Chapel Hill, North Carolina, USA; P. Konig, University of Missouri, Columbia, Missouri, USA; M. Konstan, Case Western Reserve University, Cleveland, Ohio, USA; T. Kovesi, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; J. Kramer, Oklahoma Cystic Fibrosis Center, Tulsa, Oklahoma, USA; N. Kraynack, Children's Hospital Medical Center of Akron, Akron, Ohio, USA; V. Kumar, Laurentian Hospital, Sudbury, Ontario, Canada; F. Lacaille, Hôpital Necker–Enfants Malades, Paris, France; T. Lahiri, Fletcher Allen Health Care, Burlington, Vermont, USA; C. Landon, Pediatric Diagnostic Center, Ventura, California, USA; L. Lands, Montréal Children's Hospital, Montreal, Quebec, Canada; C. Lapin, Connecticut Children's Medical Center, Hartford, Connecticut, USA; M. Larj, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, USA; A. Lavoie, Hôtel Dieu de Montréal, Montreal, Quebec, Canada; J. Ledbetter, TC Thompson Children's Hospital, Chattanooga, Tennessee, USA; R. Lee, Naval Medical Center, Portsmouth, Virginia, USA; M. Leigh, University of North Carolina, Chapel Hill, North Carolina, USA; L. Lester, University of Chicago Children's Hospital, Chicago, Illinois, USA; T. Lever, Eastern Maine Medical Center, Bangor, Maine, USA; H. Levy, Children's Hospital Boston, Boston, Massachusetts, USA; A. Lieberthal, Kaiser Permanente Southern California, Panorama City, California, USA; T. Liou, University of Utah, Salt Lake City, Utah, USA; A. Lipton, National Naval Medical Center, Bethesda, Maryland, USA; S. Lobritto, Columbia University Medical Center, New York, New York, USA; B. Lothian, Royal University Hospital, Saskatoon, Saskatchewan, Canada; D. Lougheed, Hotel Dieu Hospital, Kingston, Ontario, Canada; B. Lyttle, London Health Sciences Centre, London, Ontario, Canada; M. Macek, Charles University and University Hospital Motol, Prague, Czech Republic; K. Malhotra, Grand River Hospital, Kitchener, Ontario, Canada; J. Marcotte, Hôpital Sainte-Justine, Montreal, Quebec, Canada; E. Matouk, Montréal Chest Institute, Montreal, Quebec, Canada; M. McCarthy, Providence Medical Center, Spokane, Washington, USA; S. McColley, Children's Memorial Hospital & Northwestern University, Chicago, Illinois, USA; K. McCoy, Columbus Children's Hospital, Columbus, Ohio, USA; J. McNamara, Children's Hospitals and Clinics of Minneapolis, Minneapolis, Minnesota, USA; A. Mencin, Columbia University Medical Center, New York, New York, USA; R. Michael, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada; S. Miller, University of Mississippi Medical Center, Jackson, Mississippi, USA; M. Milot, Hôpital de Chicoutimi, Chicoutimi, Quebec, Canada; K. 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Stokes, University of Tennessee, Memphis, Tennessee, USA; B. Sullivan, Marshfield Clinic, Marshfield, Wisconsin, USA; J. Taylor-Cousar, University of New Mexico, Albuquerque, New Mexico, USA; C. Taylor, University of Sheffield, Sheffield, UK; N. Thomas, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; H. Thompson, St. Luke's Cystic Fibrosis Clinic, Boise, Idaho, USA; D. Toder, Children's Hospital of Michigan and Harper University Hospital, Detroit, Michigan, USA; E. Tullis, St. Michael's Hospital, Toronto, Ontario, Canada; N. Turcios, University of Medicine & Dentistry of New Jersey, New Brunswick, New Jersey, USA; S. Van Biervliet, Ghent University Hospital, Ghent, Belgium; R. van Wylick, Hotel Dieu Hospital, Kingston, Ontario, Canada; L. Varlotta, St. Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA; P. Vauthy, Toledo Children's Hospital, Toledo, Ohio, USA; J. Voynow, Duke University, Durham, North Carolina, USA; C. 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Abely, American Memorial Hospital, Reims, France; L. Bassinet, Centre Hospitalier Intercommunal de Créteil, Créteil, France; C. Belleguic, Hôpital Pontchaillou, Rennes, France; G. Bellon, Hôpital Femme Mère Enfant, Bron, France; K. Bessaci, American Memorial Hospital, Reims, France; A.S. Bonnel, Hôpital André Mignot, Le Chesnay, France; F. Bremont, Hôpital des Enfants de Toulouse, Toulouse, France; J. Brouard, Centre Hospitalier Universitaire de Caen, Caen, France; S. Bui, Hôpital des Enfants Groupe Pellegrin, Bordeaux, France; R. Chiron, Hôpital Arnaud de Villeneuve, Montpellier, France; R. Chumbi-Flores, Hôpital de la Tronche, Grenoble, France; J.C. Dalphin, CNRS-UFC, UMR 6249 Chrono-Environnement, Hôpital Jean Minjoz, Besançon, France; M.L. Dalphin, Centre Hospitalier Universitaire de Besançon, Besançon, France; V. David, Hôpital Mère-Enfant, Nantes, France; S. De Miranda, Hôpital Foch, Suresnes, France; J. Derelle, Hôpital d'Enfants, Vandoeuvre les Nancy, France; P. Domblides, Hôpital Haut Lévêque, Pessac, France; S. Dominique, Centre Hospitalier Universitaire Charles Nicolle, Rouen, France; J.C. Dubus, Hôpital d'Enfants de la Timone, Marseille, France; I. Durieu, UCBL1,Groupe Hospitalier Lyon Sud–Hospices Civils de Lyon, Pierre Bénite, France; S. Dury, Hôpital Maison Blanche, Reims, France; M. Ellafi, Centre Hospitalier Universitaire de Caen, Caen, France; R. Epaud, Centre Hospitalier Intercommunal de Créteil, Créteil, France; A. Fanton, Hôpital d'Enfants du Bocage, Dijon, France; M. Fayon, Hôpital des Enfants Groupe Pellegrin, Bordeaux, France; E. Fleurence, Hôpital d'Enfants, Saint-Denis de la Réunion, France; P. Foucaud, Hôpital André Mignot, Le Chesnay, France; J.L. Ginies, Centre Hospitalier Universitaire d'Angers, Angers, France; B. Godbert, Hôpital de Brabois, Vandoeuvre les Nancy, France; D. Grenet, Hôpital Foch, Suresnes, France; M. Guillot, Centre Hospitalier Robert Bisson, Lisieux, France; M.C. Heraud, Centre Hospitalier Estaing, Clermont-Ferrand, France; B. Housset, Centre Hospitalier Intercommunal de Créteil, Créteil, France; D. Hubert, Hôpital Cochin, Paris, France; F. Huet, Hôpital d'Enfants du Bocage, Dijon, France; R. Kessler, Hôpital Civil, Strasbourg, France; A. Labbé, Centre Hospitalier Estaing, Clermont-Ferrand, France; M. Laurans, Centre Hospitalier Universitaire de Caen, Caen, France; M. Le Bourgeois, Hôpital Necker–Enfants Malades, Paris, France; P. Le Roux, Hôpital Jacques Monod, Montivilliers, France; C. Llerena, Hôpital de la Tronche, Grenoble, France; G.A. Loeuille, Centre Hospitalier de Dunkerque, Dunkerque, France; C. Marguet, Centre Hospitalier Universitaire Charles Nicolle, Rouen, France; L. Melly, Hôpital Renée Sabran, Giens, France; V. Moisan-Petit, Centre Hospitalier Bretagne Atlantique, Vannes, France; A. Munck, Hôpital Robert Debré, Paris, France; M. Murris-Espin, Hôpital Larrey, Toulouse, France; R. Nove-Josserand, Groupe Hospitalier Lyon Sud–Hospices Civils de Lyon, Pierre Bénite, France; J.C. Pautard, Hôpital Nord, Amiens, France; I. Pin, INSERM, U823 Université Joseph Fourier,Hôpital de la Tronche, Grenoble, France; S. Pramil, Centre Hospitalier Universitaire Charles Nicolle, Rouen, France; A. Prevota, Hôpital Calmette, Lille, France; C. Rames, Hôpital Nord, Amiens, France; G. Rault, Centre de Perharidy, Roscoff, France; P. Reix, Hôpital Femme Mère Enfant, Bron, France; N. Remus, Centre Hospitalier Intercommunal de Créteil, Créteil, France; M. Renouil, Groupe Hospitalier Sud Réunion, Saint-Pierre de la Réunion, France; M. Reynaud-Gaubert, Hôpital Nord, Marseille, France; B. Richaud Thiriez, Hôpital Jean Minjoz, Besançon, France; M. Roussey, Université de Rennes 1, Hôpital Sud Annexe Pédiatrique, Rennes, France; I. Sermet-Gaudelus, Hôpital Necker–Enfants Malades, Paris, France; N. Stremler, Hôpital d'Enfants de la Timone, Marseille, France; M.L. Uffredi, Centre Hospitalier Bretagne Atlantique, Vannes, France; T. Urban, Centre Hospitalier Universitaire d'Angers, Angers, France; P. Vigneron, Centre Hospitalier Bretagne Sud, Lorient, France; B. Wallaert, Hôpital Calmette, Lille, France; L. Weiss, Hôpital de Hautepierre, Strasbourg, France.

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Design and conception of the GWAS-HD was carried out by L.J.S., L.S., J.M.R. and P.R.D., and the GWAS was designed by L.J.S., L.S., J.M.R., P.R.D., R.D., M.C., J.Z., H.C., P.-Y.B., A.C., M.R.K., W.K.O., F.A.W., G.R.C. and M.L.D. L.J.S., L.S., J.M.R., X.L., W.L., P.R.D., H.C., P.-Y.B., M.R.K., F.A.W., G.R.C. and R.D. prepared the manuscript. W.L., X.L., L.S., L.J.S., T.A.C., P.-Y.B. and P.-F.B. performed statistical analysis. F.A.W., L.H., S.M.B. and V.K.D. coordinated data. P.R.D., J.Z., M.C., H.C., A.C., M.R.K., W.K.O., R.G.P., J.R.S., S.D.W., L.H., S.M.B. and K.M.N. carried out recruitment and phenotyping. Genotyping was carried out by F.L., R.V.P., J.M.R., D.Z., W.K.O., R.G.P., J.R.S., L.H. and R.D. Bioinformatics were carried out by T.A.C., J.M.R., R.V.P., P.-Y.B., P.-F.B., R.G.P., J.R.S. and R.D.

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Correspondence to Lisa J Strug.

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The authors declare no competing financial interests.

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Sun, L., Rommens, J., Corvol, H. et al. Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. Nat Genet 44, 562–569 (2012). https://doi.org/10.1038/ng.2221

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