Variation in MSRA Modifies Risk of Neonatal Intestinal Obstruction in Cystic Fibrosis

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Issue Date
2012-03-15Author
Henderson, Lindsay B.
Doshi, Vishal K.
Blackman, Scott M.
Naughton, Kathleen M.
Pace, Rhonda G.
Moskovitz, Jackob
Knowles, Michael R.
Durie, Peter R.
Drumm, Mitchell L.
Cutting, Garry R.
Publisher
Public Library of Science
Type
Article
Article Version
Scholarly/refereed, publisher version
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.
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Show full item recordAbstract
Meconium 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.
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Citation
Henderson, 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
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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.