title: The NFKB1 (g.-24519delATTG) variant is associated with necrotizing enterocolitis (NEC) in premature infants.
abstract: OBJECTIVE
  While it is known that gene-environment interactions contribute to necrotizing enterocolitis (NEC) pathogenesis, characterization of genetic risk-factors that can predict NEC in preterm infants remains nascent. We hypothesized that altered intestinal immune responses arising from sequence variation in the toll-like receptor (TLR) pathway genes contribute to NEC susceptibility.
  
  
  METHODS
  Very low birth weight (VLBW) infants were recruited prospectively in a multi-center, cohort study involving collection of blood samples along with collation of clinical information. DNA obtained from blood samples was used to genotype nine single nucleotide polymorphisms (SNPs) in eight TLR pathway genes by single-base extension. Prevalence of the variant allele was compared between cases and controls using Fisher's exact test.
  
  
  RESULTS
  In our cohort of 271 infants, 15 infants (5.6%) developed NEC, and five died from it. Infants with NEC were less mature (P < 0.001), and were more likely to be African-American (P = 0.007). SNPs in the TLR2, TLR4, TLR5, TLR9, IRAK1, and TIRAP genes were not associated with NEC. The NFKB1 (g.-24519delATTG) variant was present in all infants with NEC but only in 65% of infants without NEC (P = 0.003), while the NFKBIA (g.-1004A>G) variant was present in 13.3% of infants with NEC but in 49% of infants without NEC (P = 0.007). After correcting for multiple comparisons, the NFKB1 and NFKBIA variants remained associated with NEC (P < 0.05).
  
  
  CONCLUSIONS
  These data suggest that TLR genetic variants can alter susceptibility to NEC in VLBW infants and support the hypothesis that genetically programmed differences in the innate immune response contribute to NEC pathogenesis.
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital and Health Systems, Milwaukee, Wisconsin, USA. vsampath@mcw.edu
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Sampath
authors.forename: Min
authors.initials: M
authors.lastname: Le
authors.forename: Laura
authors.initials: L
authors.lastname: Lane
authors.forename: Aloka L
authors.initials: AL
authors.lastname: Patel
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cohen
authors.forename: Pippa M
authors.initials: PM
authors.lastname: Simpson
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Garland
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Hines
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D020345:Enterocolitis, Necrotizing / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D007234:Infant, Premature; D019102:Infant, Very Low Birth Weight; D008297:Male; D052002:NF-kappa B p50 Subunit / Q000235:genetics*; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D012189:Retrospective Studies; D015398:Signal Transduction / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D051193:Toll-Like Receptors