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

Abstract

BackgroundTwin 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.MethodsGenotyping was done on Illumina BeadChip, followed by analysis using PLINK with logistic regression under an additive model.ResultsAmong 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.ConclusionGenetic variation in an intergenic region of chromosome 8 is associacted with increased risk for NEC with a mechanismthat is yet to be identified.