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.
authors.affiliation: Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rommens
authors.forename: Harriet
authors.initials: H
authors.lastname: Corvol
authors.forename: Weili
authors.initials: W
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Chiang
authors.forename: Fan
authors.initials: F
authors.lastname: Lin
authors.forename: Ruslan
authors.initials: R
authors.lastname: Dorfman
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Busson
authors.forename: Rashmi V
authors.initials: RV
authors.lastname: Parekh
authors.forename: Diana
authors.initials: D
authors.lastname: Zelenika
authors.forename: Scott M
authors.initials: SM
authors.lastname: Blackman
authors.forename: Mary
authors.initials: M
authors.lastname: Corey
authors.forename: Vishal K
authors.initials: VK
authors.lastname: Doshi
authors.forename: Lindsay
authors.initials: L
authors.lastname: Henderson
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Naughton
authors.forename: Wanda K
authors.initials: WK
authors.lastname: O'Neal
authors.forename: Rhonda G
authors.initials: RG
authors.lastname: Pace
authors.forename: Jaclyn R
authors.initials: JR
authors.lastname: Stonebraker
authors.forename: Sally D
authors.initials: SD
authors.lastname: Wood
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wright
authors.forename: Julian
authors.initials: J
authors.lastname: Zielenski
authors.forename: Annick
authors.initials: A
authors.lastname: Clement
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Drumm
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Boëlle
authors.forename: Garry R
authors.initials: GR
authors.lastname: Cutting
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Strug
mesh_terms: D026905:Amino Acid Transport Systems; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics; D017920:Antiporters / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D045823:Ileus / Q000235:genetics*; D007415:Intestinal Obstruction / Q000209:etiology; D008470:Meconium; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics; D000076988:Sulfate Transporters
chemical_list: D026905:Amino Acid Transport Systems; D026921:Amino Acid Transport Systems, Neutral; D017920:Antiporters; C505032:CFTR protein, human; C455628:SLC26A9 protein, human; C503995:SLC6A14 protein, human; C000613385:SLC9A3 protein, human; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator