Show simple item record

dc.contributor.authorHenderson, Lindsay B.
dc.contributor.authorDoshi, Vishal K.
dc.contributor.authorBlackman, Scott M.
dc.contributor.authorNaughton, Kathleen M.
dc.contributor.authorPace, Rhonda G.
dc.contributor.authorMoskovitz, Jackob
dc.contributor.authorKnowles, Michael R.
dc.contributor.authorDurie, Peter R.
dc.contributor.authorDrumm, Mitchell L.
dc.contributor.authorCutting, Garry R.
dc.date.accessioned2014-03-19T14:42:34Z
dc.date.available2014-03-19T14:42:34Z
dc.date.issued2012-03-15
dc.identifier.citationHenderson, L. B., Doshi, V. K., Blackman, S. M., Naughton, K. M., Pace, R. G., Moskovitz, J., … Cutting, G. R. (2012). Variation in MSRA Modifies Risk of Neonatal Intestinal Obstruction in Cystic Fibrosis. PLoS Genet, 8(3). http://dx.doi.org/10.1371/journal.pgen.1002580
dc.identifier.urihttp://hdl.handle.net/1808/13248
dc.description.abstractMeconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal protein content, occurs in approximately 15 percent of neonates with cystic fibrosis (CF). Analysis of twins with CF demonstrates that MI is a highly heritable trait, indicating that genetic modifiers are largely responsible for this complication. Here, we performed regional family-based association analysis of a locus that had previously been linked to MI and found that SNP haplotypes 5′ to and within the MSRA gene were associated with MI (P = 1.99×10−5 to 1.08×10−6; Bonferroni P = 0.057 to 3.1×10−3). The haplotype with the lowest P value showed association with MI in an independent sample of 1,335 unrelated CF patients (OR = 0.72, 95% CI [0.53–0.98], P = 0.04). Intestinal obstruction at the time of weaning was decreased in CF mice with Msra null alleles compared to those with wild-type Msra resulting in significant improvement in survival (P = 1.2×10−4). Similar levels of goblet cell hyperplasia were observed in the ilea of the Cftr−/− and Cftr−/−Msra−/− mice. Modulation of MSRA, an antioxidant shown to preserve the activity of enzymes, may influence proteolysis in the developing intestine of the CF fetus, thereby altering the incidence of obstruction in the newborn period. Identification of MSRA as a modifier of MI provides new insight into the biologic mechanism of neonatal intestinal obstruction caused by loss of CFTR function.
dc.description.sponsorshipThis work was supported by grants from the National Institutes of Health: NIDDK DK083551 (SMB), NHLBI HL068890 (MRK), NIGMS GM088823 and NIDDK DK027651 (MLD), NHLBI HL068927 and NIDDK DK044003 (GRC), NIA AG027363 (JM); the Cystic Fibrosis Foundation: CFF-KNOWLE00A0 (MRK), CFF-DRUMM0A00 (MLD), CFF-CUTTIN00A0 and CUTTIN06P0 (GRC); the Pediatric Endocrine Society (SMB); Genome Canada through the Ontario Genomics Institute, 2004-OGI-3-05 (PRD); the Canadian Cystic Fibrosis Foundation (PRD); and the Ontario Research Foundation (PRD).
dc.publisherPublic Library of Science
dc.rights©2012 Henderson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAlleles
dc.subjectChromosome 8
dc.subjectCystic fibrosis
dc.subjectDeath rates
dc.subjectHaplotypes
dc.subjectIleum
dc.subjectMucus
dc.subjectNeonates
dc.titleVariation in MSRA Modifies Risk of Neonatal Intestinal Obstruction in Cystic Fibrosis
dc.typeArticle
kusw.kuauthorMoskovitz, Jackob
kusw.kudepartmentDepartment of Pharmacology and Toxicology
dc.identifier.doi10.1371/journal.pgen.1002580
kusw.oaversionScholarly/refereed, publisher version
kusw.oapolicyThis item meets KU Open Access policy criteria.
dc.rights.accessrightsopenAccess


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

©2012 Henderson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Except where otherwise noted, this item's license is described as: ©2012 Henderson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.