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

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. WoodFred A. Wright, Julian Zielenski, Annick Clement, Mitchell L. Drumm, Pierre Yves Boëlle, Garry R. Cutting, Michael R. Knowles, Peter R. Durie, Lisa J. Strug

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)562-569
Number of pages8
JournalNature genetics
Volume44
Issue number5
DOIs
StatePublished - May 2012

ASJC Scopus subject areas

  • Genetics

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    Sun, L., Rommens, J. M., Corvol, H., Li, W., Li, X., Chiang, T. A., Lin, F., Dorfman, R., Busson, P. F., Parekh, R. V., Zelenika, D., Blackman, S. M., Corey, M., Doshi, V. K., Henderson, L., Naughton, K. M., O'neal, W. K., Pace, R. G., Stonebraker, J. R., ... Strug, L. J. (2012). Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. Nature genetics, 44(5), 562-569. https://doi.org/10.1038/ng.2221