Risk of Necrotizing Enterocolitis Associated With the Single Nucleotide Polymorphisms VEGF C-2578A, IL-18 C-607A, and IL-4 Receptor α-Chain A-1902G: A Validation Study in a Prospective Multicenter Cohort

Abstract

The etiology of necrotizing enterocolitis (NEC) is multifactorial and an underlying genetic predisposition to NEC is increasingly being recognized. A growing number of studies identified single nucleotide polymorphisms (SNPs) of selected genes with potential biological relevance in the development of NEC. However, few of these genetic studies have been replicated in validation cohorts. We aimed to confirm in a cohort of 358 preterm newborns (gestational age <30 weeks, 26 cases of NEC ≥ Bell stage II) the association with NEC of three candidate SNPs: the vascular endothelium growth factor (VEGF) C-2578A polymorphism (rs699947), the interleukin (IL)-18 C-607A polymorphism (rs1946518), and the IL-4 receptor α-chain (IL-4Rα) A-1902G polymorphism (rs1801275). We observed that allele and genotype frequencies of the three SNPs did not significantly differ between the infants with and without NEC. In contrast, the minor G-allele of the IL-4Rα A-1902G polymorphism was significantly less frequent in the group of 51 infants with the combined outcome NEC or death before 34 weeks postmenstrual age than in the infants without the outcome (0.206 vs. 0.331, P = 0.01). In addition, a significant negative association of the G-allele with the combined outcome NEC or death was found using the dominant (adjusted odds ratio, aOR: 0.44, 95% CI 0.21-0.92), recessive (aOR 0.15, 95% CI 0.03-0.74), and additive (aOR 0.46, 95% CI 0.26-0.80) genetic models. In conclusion our study provides further evidence that a genetic variant of the IL-4Rα gene may contribute to NEC.

Genetic Polymorphisms in NLRP3 Inflammasome-Associated Genes in Patients with B-Cell Non-Hodgkin’s Lymphoma

“…25 The IL-1β gene polymorphisms can be associated with various malignancies including gastric cancer, lung cancer and hepatocellular carcinoma, with high expression of IL-1β related to poor survival in cancers. [26][27][28] In our study, we found no significant difference in the distribution of IL-1β (rs16944) polymorphisms between the B-NHL patients and controls. There was no association between IL-1β (rs16944) polymorphisms and clinical manifestations of B-NHL patients.…”

Intestinal Stem Cell Development in the Neonatal Gut: Pathways Regulating Development and Relevance to Necrotizing Enterocolitis

“…Interestingly, both NOD2 and SIGIRR are inhibitors of TLR signaling in the neonatal intestine [ 93 , 98 ]. Genetic variants in the VEGF and other vascular genes might also be potential loci for NEC vulnerability [ 99 ]. Genome-wide transcriptome studies in intestinal tissue obtained from preterm infants with and without NEC also identify innate immune pathways as a key target in NEC [ 100 ].…”

Emerging Biomarkers for Prediction and Early Diagnosis of Necrotizing Enterocolitis in the Era of Metabolomics and Proteomics

“…Epidemiological studies showed differences in NEC prevalence among populations of different ethnic origin, while a study of twins provided evidence of a familiar predisposition to NEC (3,43,44). Genetic studies reported variations of genes and RNAs involved in NEC pathophysiology, predominantly inflammatory mediators, indicating genetic predisposition to NEC (43,(45)(46)(47)(48). A recent review by Cuna et al refers to the available data on genetic predisposition to NEC (43).…”