Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis |
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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 |
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Affiliation: | Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. |
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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. |
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