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

Variants associated with meconium ileus in cystic fibrosis (CF) were identified in 3,763 patients by GWAS. Five SNPs at two loci near SLC6A14 (min P=1.28×10(−12) at rs3788766), chr Xq23-24 and SLC26A9 (min P=9.88×10(−9) at rs4077468), chr 1q32.1 accounted for ~5% of the phenotypic variability, and w...

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Autores principales: Sun, Lei, Rommens, Johanna M, Corvol, Harriet, Li, Weili, Li, Xin, Chiang, Theodore, Lin, Fan, Dorfman, Ruslan, Busson, Pierre-François, Parekh, Rashmi V, Zelenika, Diana, Blackman, Scott, Corey, Mary, Doshi, Vishal, Henderson, Lindsay, Naughton, Kathleen, 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371103/
https://www.ncbi.nlm.nih.gov/pubmed/22466613
http://dx.doi.org/10.1038/ng.2221
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author Sun, Lei
Rommens, Johanna M
Corvol, Harriet
Li, Weili
Li, Xin
Chiang, Theodore
Lin, Fan
Dorfman, Ruslan
Busson, Pierre-François
Parekh, Rashmi V
Zelenika, Diana
Blackman, Scott
Corey, Mary
Doshi, Vishal
Henderson, Lindsay
Naughton, Kathleen
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
author_facet Sun, Lei
Rommens, Johanna M
Corvol, Harriet
Li, Weili
Li, Xin
Chiang, Theodore
Lin, Fan
Dorfman, Ruslan
Busson, Pierre-François
Parekh, Rashmi V
Zelenika, Diana
Blackman, Scott
Corey, Mary
Doshi, Vishal
Henderson, Lindsay
Naughton, Kathleen
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
author_sort Sun, Lei
collection PubMed
description Variants associated with meconium ileus in cystic fibrosis (CF) were identified in 3,763 patients by GWAS. Five SNPs at two loci near SLC6A14 (min P=1.28×10(−12) at rs3788766), chr Xq23-24 and SLC26A9 (min P=9.88×10(−9) at rs4077468), chr 1q32.1 accounted for ~5% of the phenotypic variability, and were replicated in an independent patient collection (n=2,372; P=0.001 and 0.0001 respectively). By incorporating that disease-causing mutations in CFTR alter electrolyte and fluid flux across epithelia into an hypothesis-driven genome-wide analysis (GWAS-HD), we identified the same SLC6A14 and SLC26A9 associated SNPs, while establishing 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 constituents of the apical plasma membrane where CFTR resides (P=0.0002, testing 155 apical genes jointly and replicated, 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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spelling pubmed-33711032012-07-01 Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis Sun, Lei Rommens, Johanna M Corvol, Harriet Li, Weili Li, Xin Chiang, Theodore Lin, Fan Dorfman, Ruslan Busson, Pierre-François Parekh, Rashmi V Zelenika, Diana Blackman, Scott Corey, Mary Doshi, Vishal Henderson, Lindsay Naughton, Kathleen 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 Nat Genet Article Variants associated with meconium ileus in cystic fibrosis (CF) were identified in 3,763 patients by GWAS. Five SNPs at two loci near SLC6A14 (min P=1.28×10(−12) at rs3788766), chr Xq23-24 and SLC26A9 (min P=9.88×10(−9) at rs4077468), chr 1q32.1 accounted for ~5% of the phenotypic variability, and were replicated in an independent patient collection (n=2,372; P=0.001 and 0.0001 respectively). By incorporating that disease-causing mutations in CFTR alter electrolyte and fluid flux across epithelia into an hypothesis-driven genome-wide analysis (GWAS-HD), we identified the same SLC6A14 and SLC26A9 associated SNPs, while establishing 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 constituents of the apical plasma membrane where CFTR resides (P=0.0002, testing 155 apical genes jointly and replicated, P=0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis. 2012-05 /pmc/articles/PMC3371103/ /pubmed/22466613 http://dx.doi.org/10.1038/ng.2221 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Sun, Lei
Rommens, Johanna M
Corvol, Harriet
Li, Weili
Li, Xin
Chiang, Theodore
Lin, Fan
Dorfman, Ruslan
Busson, Pierre-François
Parekh, Rashmi V
Zelenika, Diana
Blackman, Scott
Corey, Mary
Doshi, Vishal
Henderson, Lindsay
Naughton, Kathleen
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
Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis
title Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis
title_full Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis
title_fullStr Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis
title_full_unstemmed Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis
title_short Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis
title_sort multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371103/
https://www.ncbi.nlm.nih.gov/pubmed/22466613
http://dx.doi.org/10.1038/ng.2221
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