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.
Highlights
Cystic fibrosis (CF; MIM 219700, http://www.omim.org) is an autosomal recessive condition caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR; MIM 602421) gene [1]
About 15% of newborns with CF suffer from an intestinal obstruction called meconium ileus (MI), and studies in CF twins have shown that modifier genes play a substantial role in the development of this complication
CF mice lacking Msra expression had lower mortality due to intestinal obstruction at the time of transitioning to solid food and lived longer than CF mice with normal Msra, supporting the protective effect of the haplotype we observed in human CF subjects
Summary
Cystic fibrosis (CF; MIM 219700, http://www.omim.org) is an autosomal recessive condition caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR; MIM 602421) gene [1]. The earliest manifestation of CF is meconium ileus (MI), a prenatal obstruction of the small intestine at the ileocecal junction. The intestinal contents of the developing gut that form the first bowel movement, has an abnormally high protein content in CF neonates thought to be due to defective proteolysis [2,3,4]. Impaction of the tenacious meconium results in intestinal obstruction in approximately 15% of CF newborns. This complication presents as abdominal distention, failure to pass meconium, and vomiting and was near universally fatal in CF newborns until effective treatment (enema or surgery) was developed. The long term effects of MI have been a matter of debate as some investigators have reported worse outcomes while others observed no significant differences from CF subjects without MI [5,6,7]
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