title: A functional ATG16L1 (T300A) variant is associated with necrotizing enterocolitis in premature infants.
abstract: BACKGROUND
  The genetic basis of dysfunctional immune responses in necrotizing enterocolitis (NEC) remains unknown. We hypothesized that variants in nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs) and autophagy (ATG) genes modulate vulnerability to NEC.
  
  
  METHODS
  We genotyped a multi-center cohort of premature infants with and without NEC for NOD1, NOD2, ATG16L1, CARD8, and NLRP3 variants. Chi-square tests and logistic regression were used for statistical analysis.
  
  
  RESULTS
  In our primary cohort (n = 1,015), 86 (8.5%) infants developed NEC. The A allele of the ATG16L1 (Thr300Ala) variant was associated with increased NEC (AA vs. AG vs. GG; 11.3 vs. 8.4 vs. 4.8%, P = 0.009). In regression models for NEC that adjusted for epidemiological confounders, GA (P = 0.033) and the AA genotype (P = 0.038) of ATG16L1 variant were associated with NEC. The association between the A allele of the ATG16L1 variant and NEC remained significant among Caucasian infants (P = 0.02). In a replication cohort (n = 259), NEC rates were highest among infants with the AA genotype but did not reach statistical significance.
  
  
  CONCLUSIONS
  We report a novel association between a hypomorphic variant in an autophagy gene (ATG16L1) and NEC in premature infants. Our data suggest that decreased autophagy arising from genetic variants may confer protection against NEC.
authors.affiliation: Department of Pediatrics, Children's Mercy, Kansas City, Missouri.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Sampath
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.|Current affiliation: St. Christopher's Hospital for Children/Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Vineet
authors.initials: V
authors.lastname: Bhandari
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.|Current affiliation: John Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jessica
authors.initials: J
authors.lastname: Berger
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Daniel
authors.initials: D
authors.lastname: Merchant
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Liyun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Ladd
authors.affiliation: Department of Pediatrics, Children's Mercy, Kansas City, Missouri.
authors.forename: Heather
authors.initials: H
authors.lastname: Menden
authors.affiliation: Department of Pediatrics, St Joseph Hospital, Milwaukee, Wisconsin.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Garland
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
authors.affiliation: Department of Pediatrics, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.
authors.forename: Neil
authors.initials: N
authors.lastname: Mulrooney
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Harbor, Michigan.
authors.forename: Michael
authors.initials: M
authors.lastname: Quasney
authors.affiliation: Department of Pediatrics, Iowa Children's Hospital, Iowa City, Iowa.
authors.forename: John
authors.initials: J
authors.lastname: Dagle
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Pascal M
authors.initials: PM
authors.lastname: Lavoie
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Pippa
authors.initials: P
authors.lastname: Simpson
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Harbor, Michigan.
authors.forename: Mary
authors.initials: M
authors.lastname: Dahmer
mesh_terms: D000483:Alleles; D001343:Autophagy; D000071183:Autophagy-Related Proteins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D015331:Cohort Studies; D020345:Enterocolitis, Necrotizing / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D020641:Polymorphism, Single Nucleotide; D044465:White People
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins