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Article: Modifier gene study of meconium ileus in cystic fibrosis: Statistical considerations and gene mapping results
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TitleModifier gene study of meconium ileus in cystic fibrosis: Statistical considerations and gene mapping results
 
AuthorsDorfman, R11
Li, W11
Sun, L8 11
Lin, F11
Wang, Y11
Sandford, A7
Paré, PD7
McKay, K12
Kayserova, H9
Piskackova, T6
MacEk, M6
Czerska, K4
Sands, D4
Tiddens, H2
Margarit, S5
Repetto, G5
Sontag, MK10
Accurso, FJ10
Blackman, S1
Cutting, GR1
Tsui, LC11 3
Corey, M8 11
Durie, P11
Zielenski, J11
Strug, LJ8 11
 
Issue Date2009
 
PublisherSpringer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00439/index.htm
 
CitationHuman Genetics, 2009, v. 126 n. 6, p. 763-778 [How to Cite?]
DOI: http://dx.doi.org/10.1007/s00439-009-0724-8
 
AbstractCystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16-20% of CF newborns, providing linkage and association results from large family and case-control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case-control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy-Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up. © 2009 Springer-Verlag.
 
ISSN0340-6717
2013 Impact Factor: 4.522
 
DOIhttp://dx.doi.org/10.1007/s00439-009-0724-8
 
PubMed Central IDPMC2888886
 
ISI Accession Number IDWOS:000271924900004
Funding AgencyGrant Number
Genome Canada through the Ontario Genomics Institute2004-OGI-3-05
Canadian Cystic Fibrosis Foundation
Ontario Research Fund
NIHHG-0004314
Natural Sciences and Engineering Research Council
Canadian Institutes of Health Research
Ontario Women's Health Council
VZFNM00064203
Funding Information:

This project was supported by Genome Canada through the Ontario Genomics Institute per research agreement 2004-OGI-3-05, by the Canadian Cystic Fibrosis Foundation, by the Ontario Research Fund-Research Excellence Program. L.J. Strug is supported by the NIH (HG-0004314) and the Natural Sciences and Engineering Research Council. R. Dorfman was supported by the joint Fellowship of Canadian Institutes of Health Research and Ontario Women's Health Council. Support by VZFNM00064203 to Milan Macek. The authors express gratitude to all CF patients and their families for participating in this study. The authors thank Nicole Anderson, Jennifer Breaton, Mary Cristofi, Roxanne Rousseau, and Michael Van Spall for their exceptional effort in recruiting and ascertaining Canadian CF families for the study, as well Drs. Miroslava Balascakova, Vera Vavrova and Dana Zemkova for provision of patients with MI. The authors are indebted to the following individuals from member institutions of the Canadian Consortium for CF Genetic Studies for ascertaining patient data and blood samples from CF patients and their families: S. Aaron, P. Barrett, B. Beaurivage, Y. Berthiaume, P. Bigonesse, M. Boland, L. Boucher, J. Boucher, S. Bourgh, F. Brosseau, N.E. Brown, C. Brunoro, N. Bureau, A. Cantin, L. Charette, G. Cote, A. Dale, G. Davidson, K. Devesceri, R. Dicaire, V. Fauvel, A. Freitag, D. N. Garey, M. Gaul, W. Gervais, J. Gjevre, F. Gosse, A. Gravelle, B. Habbick, R. Hennessey, S. B. Holmes, J. Hopkins, D. Hughes, M. Jackson, J. Jacob, A. Jeanneret, P. Kean, W. Kepron, T. Kovesi, V. J. Kumar, L. Lands, M. LaPerriere, J. Leong, R. Levesque, D. Lougheed, M. Lowe, B. Lyttle, K. Malhotra, J. E. Marcotte, S. Marsolais, C. Martineau, E. Matouk, D. McCulloch, R. T. Michael, M. Montgomery, R. Morris, E. M. Nakielna, F. Paquet, H. Pasterkamp, N. Patterson, L. Pedder, L. Peterson, N. Petit, C. Piche, M. Plante, H. R. Rabin, K. Ramlall, F. Raymong, L. Rivard, G. Rivard, M. Roussin, M. Ruel, J. Salgado, L. Semple, E. Sheppard, F. Simard, A. Smith, M. Solomon, R. Stackhouse, J. Tabak, L. Taylor, A. Tsang, E. Tullis, C. Turtle, K. Vandamheen, M. van Spall, R. van Wylick, I. Waters, T. Wells, S. Wiltse, and P. Zuberbuhler.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorDorfman, R
 
dc.contributor.authorLi, W
 
dc.contributor.authorSun, L
 
dc.contributor.authorLin, F
 
dc.contributor.authorWang, Y
 
dc.contributor.authorSandford, A
 
dc.contributor.authorParé, PD
 
dc.contributor.authorMcKay, K
 
dc.contributor.authorKayserova, H
 
dc.contributor.authorPiskackova, T
 
dc.contributor.authorMacEk, M
 
dc.contributor.authorCzerska, K
 
dc.contributor.authorSands, D
 
dc.contributor.authorTiddens, H
 
dc.contributor.authorMargarit, S
 
dc.contributor.authorRepetto, G
 
dc.contributor.authorSontag, MK
 
dc.contributor.authorAccurso, FJ
 
dc.contributor.authorBlackman, S
 
dc.contributor.authorCutting, GR
 
dc.contributor.authorTsui, LC
 
dc.contributor.authorCorey, M
 
dc.contributor.authorDurie, P
 
dc.contributor.authorZielenski, J
 
dc.contributor.authorStrug, LJ
 
dc.date.accessioned2011-11-24T09:07:03Z
 
dc.date.available2011-11-24T09:07:03Z
 
dc.date.issued2009
 
dc.description.abstractCystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16-20% of CF newborns, providing linkage and association results from large family and case-control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case-control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy-Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up. © 2009 Springer-Verlag.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationHuman Genetics, 2009, v. 126 n. 6, p. 763-778 [How to Cite?]
DOI: http://dx.doi.org/10.1007/s00439-009-0724-8
 
dc.identifier.citeulike5543552
 
dc.identifier.doihttp://dx.doi.org/10.1007/s00439-009-0724-8
 
dc.identifier.epage778
 
dc.identifier.isiWOS:000271924900004
Funding AgencyGrant Number
Genome Canada through the Ontario Genomics Institute2004-OGI-3-05
Canadian Cystic Fibrosis Foundation
Ontario Research Fund
NIHHG-0004314
Natural Sciences and Engineering Research Council
Canadian Institutes of Health Research
Ontario Women's Health Council
VZFNM00064203
Funding Information:

This project was supported by Genome Canada through the Ontario Genomics Institute per research agreement 2004-OGI-3-05, by the Canadian Cystic Fibrosis Foundation, by the Ontario Research Fund-Research Excellence Program. L.J. Strug is supported by the NIH (HG-0004314) and the Natural Sciences and Engineering Research Council. R. Dorfman was supported by the joint Fellowship of Canadian Institutes of Health Research and Ontario Women's Health Council. Support by VZFNM00064203 to Milan Macek. The authors express gratitude to all CF patients and their families for participating in this study. The authors thank Nicole Anderson, Jennifer Breaton, Mary Cristofi, Roxanne Rousseau, and Michael Van Spall for their exceptional effort in recruiting and ascertaining Canadian CF families for the study, as well Drs. Miroslava Balascakova, Vera Vavrova and Dana Zemkova for provision of patients with MI. The authors are indebted to the following individuals from member institutions of the Canadian Consortium for CF Genetic Studies for ascertaining patient data and blood samples from CF patients and their families: S. Aaron, P. Barrett, B. Beaurivage, Y. Berthiaume, P. Bigonesse, M. Boland, L. Boucher, J. Boucher, S. Bourgh, F. Brosseau, N.E. Brown, C. Brunoro, N. Bureau, A. Cantin, L. Charette, G. Cote, A. Dale, G. Davidson, K. Devesceri, R. Dicaire, V. Fauvel, A. Freitag, D. N. Garey, M. Gaul, W. Gervais, J. Gjevre, F. Gosse, A. Gravelle, B. Habbick, R. Hennessey, S. B. Holmes, J. Hopkins, D. Hughes, M. Jackson, J. Jacob, A. Jeanneret, P. Kean, W. Kepron, T. Kovesi, V. J. Kumar, L. Lands, M. LaPerriere, J. Leong, R. Levesque, D. Lougheed, M. Lowe, B. Lyttle, K. Malhotra, J. E. Marcotte, S. Marsolais, C. Martineau, E. Matouk, D. McCulloch, R. T. Michael, M. Montgomery, R. Morris, E. M. Nakielna, F. Paquet, H. Pasterkamp, N. Patterson, L. Pedder, L. Peterson, N. Petit, C. Piche, M. Plante, H. R. Rabin, K. Ramlall, F. Raymong, L. Rivard, G. Rivard, M. Roussin, M. Ruel, J. Salgado, L. Semple, E. Sheppard, F. Simard, A. Smith, M. Solomon, R. Stackhouse, J. Tabak, L. Taylor, A. Tsang, E. Tullis, C. Turtle, K. Vandamheen, M. van Spall, R. van Wylick, I. Waters, T. Wells, S. Wiltse, and P. Zuberbuhler.

 
dc.identifier.issn0340-6717
2013 Impact Factor: 4.522
 
dc.identifier.issue6
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC2888886
 
dc.identifier.pmid19662435
 
dc.identifier.scopuseid_2-s2.0-71349088574
 
dc.identifier.spage763
 
dc.identifier.urihttp://hdl.handle.net/10722/143355
 
dc.identifier.volume126
 
dc.languageeng
 
dc.publisherSpringer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00439/index.htm
 
dc.publisher.placeGermany
 
dc.relation.ispartofHuman Genetics
 
dc.relation.referencesReferences in Scopus
 
dc.rightsThe original publication is available at www.springerlink.com
 
dc.subject.meshChromosome Mapping
 
dc.subject.meshChromosomes, Human, Pair 12
 
dc.subject.meshCystic Fibrosis - genetics
 
dc.subject.meshIleus - genetics
 
dc.subject.meshMeconium
 
dc.titleModifier gene study of meconium ileus in cystic fibrosis: Statistical considerations and gene mapping results
 
dc.typeArticle
 
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Author Affiliations
  1. Johns Hopkins University
  2. Erasmus University Medical Center
  3. The University of Hong Kong
  4. Instytut Matki I Dziecka
  5. Universidad del Desarrollo
  6. Motol University Hospital
  7. The University of British Columbia
  8. University of Toronto
  9. Institute of Molecular Physiology and Genetics Slovak Academy of Sciences
  10. University of Colorado Health Sciences Center
  11. Hospital for Sick Children University of Toronto
  12. Children's Hospital At Westmead