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

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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 × 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.


  • 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

publication date

  • May 2012

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