Surgical Necrotizing Enterocolitis in Extremely Premature Neonates is Associated with Genetic Variations in an Intergenic Region of Chromosome Eight

BACKGROUND: Twin studies suggest that genetic factors may account for up to 50% increased risk for necrotizing enterocolitis (NEC), but genome-wide association studies (GWAS) 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 (<1000g, >401g) neonates, 30 had surgical NEC. 261 single nucleotide polymorphisms (SNPs) showed association with NEC at P<0.05, of which 35 were significant at P<10(−7). Minor allele(s) in a a cluster of SNPs spanning a 43 Kb region of chromosome 8 (8q23.3) conferred an odds ratio of 4.72 (95% CI 2.51-8.88) for elevated risk of NEC. Two smaller clusters on chromosome 14 and chromosome 11 exhibited P values 10(−7) – 10(−8). The chromosome 8 cluster is in an intergenic 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 reading frame corresponding to a long interspersed element-1 (LINE-1) retrotransposable element. CONCLUSION: Genetic variation in an intergenic region of chromosome 8 is associacted with increased risk for NEC with a mechanismthat is yet to be identified.