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

• Published in: Nature genetics Vol. 44; no. 5; pp. 562 - 569
• Main Authors: Sun, Lei, Rommens, Johanna M, Corvol, Harriet, Li, Weili, Li, Xin, Chiang, Theodore A, Lin, Fan, Dorfman, Ruslan, Busson, Pierre-François, Parekh, Rashmi V, Zelenika, Diana, Blackman, Scott M, Corey, Mary, Doshi, Vishal K, Henderson, Lindsay, Naughton, Kathleen M, O'Neal, Wanda K, Pace, Rhonda G, Stonebraker, Jaclyn R, Wood, Sally D, Wright, Fred A, Zielenski, Julian, Clement, Annick, Drumm, Mitchell L, Boëlle, Pierre-Yves, Cutting, Garry R, Knowles, Michael R, Durie, Peter R, Strug, Lisa J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2012; Nature Publishing Group
• Subjects: 631/208/205/2138; 631/208/2489/144; Agriculture; Amino Acid Transport Systems; Amino Acid Transport Systems, Neutral - genetics; Animal Genetics and Genomics; Antiporters - genetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Membrane - metabolism; Cystic fibrosis; Cystic Fibrosis - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Errors of metabolism; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Function; Genes; Genetic Predisposition to Disease; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genomes; Genotype; Human Genetics; Humans; Ileus - genetics; Intestinal Obstruction - etiology; letter; Life Sciences; Meconium; Medical sciences; Membranes; Metabolic diseases; Miscellaneous hereditary metabolic disorders; Other diseases. Semiology; Plasma; Polymorphism, Single Nucleotide - genetics; Rodents; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Sulfate Transporters; France; Newborn diseases; Respiratory disease; Plasma membrane; Metabolic diseases; Digestive diseases; Intestinal disease; Cystic fibrosis; Meconium ileus; Genetic disease; Pancreatic disease
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.2221

Lisa Strug and colleagues report a genome-wide association study for meconium ileus in individuals with cystic fibrosis. Conventional genome-wide approaches identified variants in
SLC26A9
and
SLC6A14
associated with meconium ileus. The authors also performed a hypothesis-driven genome-wide association study (HD-GWAS) that upweighted 3,814 SNPs within 10 kb of 155 genes expressed in the apical plasma membrane. The HD-GWAS identified variants near
SLC9A3
associated with meconium ileus.
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.