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.

Estimation of Neonatal Intestinal Perforation Associated with Necrotizing Enterocolitis by Machine Learning Reveals New Key Factors

“…Recent studies performed in twins have suggested that a genetic variation in an intergenic region of chromosome 8, labeled as the “NECRISK” region may be associated with increased risk for surgical NEC. Although no specific genes have been identified, pathway analyses have indicated possible pathways related to growth factor, calcium, and G-protein signaling, and others associated with inflammation that may contribute to NEC complications [ 45 ].…”

Major Chromosomal Abnormalities and Necrotizing Enterocolitis: Is there a Link?

“…Of the contributing genetic factors, the association of mutations or single-nucleotide polymorphisms (SNPs) in individual genes with the incidence of NEC have been most investigated; reviewed by Cuna et al 3 Additionally, association between NEC with genome-wide SNPs and with organ-specific and gene-specific epigenetic changes have been analyzed, which have been summarized in other reviews in this issue. [4][5][6] Numerical Chromosomal Disorders and NEC 7 Intriguingly, there were 20 (16%) cases of NEC in the T21 cohort, but there were none in the T13 and T18 cohorts among neonates that survived ≥12 h after birth. These differences could be potentially explained by the significantly higher percentage of neonates with gestational ages <26 weeks in the T21 group (n = 22, 16%) than in the T18 group (n = 3, 3%); T13 was not significantly different (n = 2, 6%).…”

New insights into necrotizing enterocolitis: From laboratory observation to personalized prevention and treatment

“…Other groups have focused on assessing the microbiota in the stool of patients with NEC [11], in a search for signature bacterial changes that can be readily assessed and which may provide clues to the onset of NEC development [64,65]. More recently, laboratories have focused on identifying various genetic risk factors for NEC [66], which has led to an understanding that polymorphisms in TLR4 associated genes, as well as others, may be linked to disease progression [30][31][32]. Finally, investigators are using more advanced diagnostic modalities including near-infrared spectroscopy to predict the course of NEC, and to identify its development at earlier stages based upon patterns of blood flow and tissue perfusion [67,68].…”