title: Variation in MSRA modifies risk of neonatal intestinal obstruction in cystic fibrosis.
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.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Henderson
authors.forename: Vishal K
authors.initials: VK
authors.lastname: Doshi
authors.forename: Scott M
authors.initials: SM
authors.lastname: Blackman
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Naughton
authors.forename: Rhonda G
authors.initials: RG
authors.lastname: Pace
authors.forename: Jackob
authors.initials: J
authors.lastname: Moskovitz
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Drumm
authors.forename: Garry R
authors.initials: GR
authors.lastname: Cutting
mesh_terms: D000818:Animals; D003550:Cystic Fibrosis / Q000150:complications / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D056726:Genetic Association Studies; D020397:Goblet Cells / Q000473:pathology; D006239:Haplotypes; D006801:Humans; D007415:Intestinal Obstruction / Q000150:complications / Q000235:genetics / Q000378:metabolism; D051150:Methionine Sulfoxide Reductases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018181:Mice, Inbred CFTR; D020641:Polymorphism, Single Nucleotide
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase