The NFKB1 (g.-24519delATTG) Variant is Associated with Necrotizing Enterocolitis (NEC) in Premature Infants

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. Materials and 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.