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.
Highlights
Necrotizing enterocolitis (NEC) is the leading cause of morbidity and mortality from gastrointestinal disease in very and extremely preterm infants [1, 2]
A total number of 358 preterm infants (26 necrotizing enterocolitis (NEC) cases) were genotyped for the three single nucleotide polymorphisms (SNPs), but genotype of vascular endothelium growth factor (VEGF) C-2578A SNP failed in 9 infants (1 from the NEC group) and genotype of IL-18 C-607A SNP failed in 1 infant without NEC
We adjusted for GA, BW, Apgar score after at 1 and 5 min, TABLE 2 | Baseline characteristics and neonatal complications in preterm infants with and without the combined outcome NEC or death before 34 weeks of corrected gestational age
Summary
Necrotizing enterocolitis (NEC) is the leading cause of morbidity and mortality from gastrointestinal disease in very and extremely preterm infants [1, 2]. As recently reviewed by Cuna et al, the candidate gene approach has been used in most studies on the genetics of NEC [3] Using this approach, a growing number of studies investigated single nucleotide polymorphisms (SNPs) of selected genes based on a-priori hypothesis of relevance to NEC. A growing number of studies investigated single nucleotide polymorphisms (SNPs) of selected genes based on a-priori hypothesis of relevance to NEC These studies focused on mediators involved in the regulation of immune/inflammatory responses, such as toll like receptors, interleukins (ILs), tumor necrosis factor, or nuclear factor-kappa beta, and in the control of intestinal microcirculation, such as nitric oxide synthase, or vascular endothelium growth factor (VEGF) [3]. We performed our investigation in a cohort of preterm infants from four neonatal intensive care units located in three different European countries (Spain, Italy, and the Netherlands) [16, 17]
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