Variation in msra modifies risk of neonatal intestinal obstruction in cystic fibrosis

Lindsay B. Henderson, Vishal K. Doshi, Scott Blackman, Kathleen M. Naughton, Rhonda G. Pace, Jackob Moskovitz, Michael R. Knowles, Peter R. Durie, Mitchell L. Drumm, Garry R Cutting

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere1002580
JournalPLoS Genetics
Volume8
Issue number3
DOIs
StatePublished - Mar 2012

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Meconium
Intestinal Obstruction
cystic fibrosis
intestinal obstruction
Ileus
Cystic Fibrosis
weaning
neonate
antioxidant
allele
enzyme
protein
gene
Haplotypes
modifiers (genes)
Newborn Infant
Goblet Cells
haplotypes
neonates
analysis

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Variation in msra modifies risk of neonatal intestinal obstruction in cystic fibrosis. / Henderson, Lindsay B.; Doshi, Vishal K.; Blackman, Scott; Naughton, Kathleen M.; Pace, Rhonda G.; Moskovitz, Jackob; Knowles, Michael R.; Durie, Peter R.; Drumm, Mitchell L.; Cutting, Garry R.

In: PLoS Genetics, Vol. 8, No. 3, e1002580, 03.2012.

Research output: Contribution to journalArticle

Henderson, LB, Doshi, VK, Blackman, S, Naughton, KM, Pace, RG, Moskovitz, J, Knowles, MR, Durie, PR, Drumm, ML & Cutting, GR 2012, 'Variation in msra modifies risk of neonatal intestinal obstruction in cystic fibrosis', PLoS Genetics, vol. 8, no. 3, e1002580. https://doi.org/10.1371/journal.pgen.1002580
Henderson, Lindsay B. ; Doshi, Vishal K. ; Blackman, Scott ; Naughton, Kathleen M. ; Pace, Rhonda G. ; Moskovitz, Jackob ; Knowles, Michael R. ; Durie, Peter R. ; Drumm, Mitchell L. ; Cutting, Garry R. / Variation in msra modifies risk of neonatal intestinal obstruction in cystic fibrosis. In: PLoS Genetics. 2012 ; Vol. 8, No. 3.
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