Surgical necrotizing enterocolitis in extremely premature neonates is associated with genetic variations in an intergenic region of chromosome 8

BACKGROUND: Twin studies suggest that genetic factors may account for up to 50% increased risk for necrotizing enterocolitis (NEC), but genome wide association studies for NEC are lacking. METHODS: Genotyping was done on Illumina BeadChip, followed by analysis using PLINK with logistic regression under an additive model. RESULTS: Among 751 extremely-low-birth-weight (<1,000 g, >401 g) neonates, 30 had surgical NEC Two hundred and sixty-one single-nucleotide polymorphisms (SNPs) showed association with NEC at P<005, of which 35 were significant at P< 10 (-7) Minor allele(s) in a cluster of SNPs spanning a 43-kb region of chromosome 8 (8q23 3) conferred an odds ratio of 4.72 (95% confidence interval (Cl): 2.51-8.88) for elevated risk of NEC Two smaller clusters on chromosome 14 and chromasome 11 exhibited P values of 10(-7)-10(-8). The chromosome 8 cluster is in an intergeinc region between CUB and Sushi multiple domains 3 (-1.43 Mb) and trichorhinophalangeal syndrome I (+542 kb). RNA sequencing in this region identified a potential novel open-ieadmg frame corresponding to a long interspersed element-1 retrotransposable element. CONCLUSION: Genetic variation in an intergenic region of chromosome 8 is associated with increased risk for NEC with a mechanism that is yet to be identified.