Genetic predisposition to necrotizing enterocolitis in premature infants: Current knowledge, challenges, and future directions

Abstract

The role of genetics in the pathogenesis of necrotizing enterocolitis (NEC) was initially informed by epidemiological data indicating differences in prevalence among different ethnic groups as well as concordance in twins. These early observations, together with major advances in genomic research, paved the way for studies that begin to reveal the contribution of genetics to NEC. Using the candidate gene- or pathway approach, several potential pathogenic variants for NEC in premature infants have already been identified. More recently, exome- and genome-wide association study for NEC has also been completed. These advances, however, are tempered by the lack of adequately powered replication cohorts to validate the accuracy of these discoveries. Despite many challenges, genetic research in NEC is expected to increase, providing new insights into its pathogenesis and bringing the promise of personalized care closer to reality. In this review we provide a summary of genetic studies in NEC along with defining the challenges and possible future approaches.

Necrotizing enterocolitis

“…Furthermore, results from another large national dataset show a linear relationship between PMA at diagnosis across all preterm gestational ages . Therefore, an early initial perinatal event along with subsequent postnatal factors interacting with an immature intestine are likely culprits in the etiology of NEC, especially in a genetically predisposed infant …”

“…4 Therefore, an early initial perinatal event along with subsequent postnatal factors interacting with an immature intestine are likely culprits in the etiology of NEC, especially in a genetically predisposed infant. 33 The preterm infant has an immature intestinal barrier with impaired epithelial cell junctions, mucus layer mucin, trefoil factor deficiencies, and decreased Paneth cell number and function. 34,35 Accumulating evidence suggests the pathogenesis of NEC is multifactorial, and necrosis is the downstream product of what may be several upstream pathophysiologic processes.…”

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

“…Keywords: VEGF, IL-18, IL-4 receptor α-chain, polymorphisms, necrotizing enterocolitis, preterm INTRODUCTION Necrotizing enterocolitis (NEC) is the leading cause of morbidity and mortality from gastrointestinal disease in very and extremely preterm infants (1,2). As extensively discussed in several exhaustive reviews, the etiology of NEC is multifactorial and largely related to immaturity of the gastrointestinal tract (1)(2)(3)(4)(5)(6)(7)(8)(9). Besides low gestational age (GA), a complex interplay of other factors, such as type of feeding, gut dysbiosis, the high susceptibility of intestinal mucosal surface to inflammatory processes, or intestinal hypoperfusion may contribute to the pathogenesis of NEC (1)(2)(3)(4)(5)(6)(7)(8)(9).…”

“…Besides low gestational age (GA), a complex interplay of other factors, such as type of feeding, gut dysbiosis, the high susceptibility of intestinal mucosal surface to inflammatory processes, or intestinal hypoperfusion may contribute to the pathogenesis of NEC (1)(2)(3)(4)(5)(6)(7)(8)(9). Nevertheless, NEC affects a minority of (very) preterm infants and clinical risk factors provide a limited explanation of the inter-individual variability in NEC susceptibility (3,10). In the last years, an underlying genetic predisposition to NEC is increasingly being recognized (3,10,11).…”

“…Nevertheless, NEC affects a minority of (very) preterm infants and clinical risk factors provide a limited explanation of the inter-individual variability in NEC susceptibility (3,10). In the last years, an underlying genetic predisposition to NEC is increasingly being recognized (3,10,11).…”