@article{9a5da2d7b8c84312af69121e66e3962e,
title = "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.",
author = "Lei Sun and Rommens, {Johanna M.} and Harriet Corvol and Weili Li and Xin Li and Chiang, {Theodore A.} and Fan Lin and Ruslan Dorfman and Busson, {Pierre Fran{\c c}ois} and Parekh, {Rashmi V.} and Diana Zelenika and Blackman, {Scott M.} and Mary Corey and Doshi, {Vishal K.} and Lindsay Henderson and Naughton, {Kathleen M.} and O'neal, {Wanda K.} and Pace, {Rhonda G.} and Stonebraker, {Jaclyn R.} and Wood, {Sally D.} and Wright, {Fred A.} and Julian Zielenski and Annick Clement and Drumm, {Mitchell L.} and Bo{\"e}lle, {Pierre Yves} and Cutting, {Garry R.} and Knowles, {Michael R.} and Durie, {Peter R.} and Strug, {Lisa J.}",
note = "Funding Information: 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; Universit{\'e} Pierre et Marie Curie Paris; Agence Nationale de la Recherche (R09186DS to H.C.), Direction G{\'e}n{\'e}rale de la Sant{\'e}; Association Vaincre la Mucoviscidose, Chancellerie des Universit{\'e}s (Legs Poix); Association Agir Informer Contre la Mucoviscidose; and Groupement d{\textquoteright}Int{\'e}r{\^e}t 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{\textquoteright}s Health Council.",
year = "2012",
month = may,
doi = "10.1038/ng.2221",
language = "English (US)",
volume = "44",
pages = "562--569",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "5",
}