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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-05

AUTHORS

Lei Sun, Johanna M Rommens, Harriet Corvol, Weili Li, Xin Li, Theodore A Chiang, Fan Lin, Ruslan Dorfman, Pierre-François Busson, Rashmi V Parekh, Diana Zelenika, Scott M Blackman, Mary Corey, Vishal K Doshi, Lindsay Henderson, Kathleen M Naughton, Wanda K O'Neal, Rhonda G Pace, Jaclyn R Stonebraker, Sally D Wood, Fred A Wright, Julian Zielenski, Annick Clement, Mitchell L Drumm, Pierre-Yves Boëlle, Garry R Cutting, Michael R Knowles, Peter R Durie, Lisa J Strug

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. More... »

PAGES

562

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ng.2221

DOI

http://dx.doi.org/10.1038/ng.2221

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1053601402

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/22466613


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466 Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA.
467 rdf:type schema:Organization
468 https://www.grid.ac/institutes/grid.418135.a schema:alternateName Centre National de Génotypage
469 schema:name Centre National de Génotypage (CNG), Commisariat à l'Energie Atomique (CEA), Evry, France.
470 rdf:type schema:Organization
471 https://www.grid.ac/institutes/grid.42327.30 schema:alternateName Hospital for Sick Children
472 schema:name Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
473 Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada.
474 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
475 rdf:type schema:Organization
476 https://www.grid.ac/institutes/grid.462844.8 schema:alternateName Sorbonne University
477 schema:name Biostatistics Department, AP-HP, Saint-Antoine Hospital, INSERM, Unité Mixte de Recherche (UMR) S707, Paris, France.
478 Pediatric Pulmonary Department, Hospital Trousseau, Assistance Publique-Hôpitaux de Paris (AP-HP), Institut National de la Santé et la Recherche Médicale (INSERM), U938, Paris, France.
479 Pierre et Marie Curie University–Paris 6, Paris, France.
480 rdf:type schema:Organization
481 https://www.grid.ac/institutes/grid.67105.35 schema:alternateName Case Western Reserve University
482 schema:name Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA.
483 Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio, USA.
484 rdf:type schema:Organization
 




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