Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782235177777364992 |
---|---|
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. |
format | Online Article Text |
id | pubmed-3371103 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT sunlei multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT rommensjohannam multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT corvolharriet multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT liweili multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT lixin multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT chiangtheodore multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT linfan multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT dorfmanruslan multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT bussonpierrefrancois multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT parekhrashmiv multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT zelenikadiana multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT blackmanscott multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT coreymary multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT doshivishal multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT hendersonlindsay multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT naughtonkathleen multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT onealwandak multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT pacerhondag multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT stonebrakerjaclynr multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT woodsallyd multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT wrightfreda multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT zielenskijulian multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT clementannick multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT drummmitchelll multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT boellepierreyves multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT cuttinggarryr multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT knowlesmichaelr multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT duriepeterr multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis AT struglisaj multipleapicalplasmamembraneconstituentsareassociatedwithsusceptibilitytomeconiumileusinindividualswithcysticfibrosis |