Journal
NATURE GENETICS
Volume 44, Issue 5, Pages 562-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2221
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Funding
- Genome Canada, through the Ontario Genomics Institute [2004-OGI-3-05]
- Ontario Research Fund, Research Excellence Program
- University of Toronto McLaughlin Centre
- Ontario Ministry of Research and Innovation
- Natural Sciences and Engineering Research Council
- Cystic Fibrosis Canada (CFC)
- Natural Sciences and Engineering Research Council (NSERC) [F250053-2008]
- Canadian Institutes of Health Research (CIHR) [MOP 84287, MOP 258916]
- Lloyd Carr-Harris Foundation
- US National Institutes of Health [R01 HL68927, K23 DK083551, R01 HL068890, R01 DK066368, R01 HL095396, HG-0004314]
- US CFF [CUTTIN06P0, R025-CR07, KNOWLE00A0, RDP-R026-CR07, DRUMM0A00]
- Flight Attendant Medical Research Institute [FAMRI2006]
- Lawson Wilkins Pediatric Endocrine Society
- INSERM
- AP-HP
- Universite Pierre et Marie Curie Paris
- Agence Nationale de la Recherche [R09186DS]
- Direction Generale de la Sante
- Association Vaincre la Mucoviscidose, Chancellerie des Universites (Legs Poix)
- Association Agir Informer Contre la Mucoviscidose
- Groupement d'Interet Scientifique (GIS)-Institut des Maladies Rares
- US CFF
- CIHR
- Ontario Women's Health Council
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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 x 10(-12) at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 x 10(-9) at rs4077468) accounted for similar to 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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