A functional ATG16L1 (T300A) variant is associated with necrotizing enterocolitis in premature infants

Sampath, Venkatesh; Bhandari, Vineet; Berger, Jéssica; Merchant, Daniel; Zhang, Liyun; Ladd, Mihoko; Menden, Heather; Garland, Jeffery S.; Ambalavanan, Namasivayam; Mulrooney, Neil; Quasney, Michael W.; Dagle, John M.; Lavoie, Pascal M.; Simpson, Pippa; Dahmer, Mary K.

doi:10.1038/pr.2016.260

Cited by 40 publications

(35 citation statements)

References 42 publications

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“…While TLR SNPs have been examined in preterm sepsis, the NOD1 , NLRP3 , and ATG16L1 SNPs have not been studied before [4,5]. Reports demonstrating associations between NLR variants and NEC support our conclusions that NLR genes are potential loci for bacterial diseases in premature infants [6,10]. …”

Section: Discussionsupporting

confidence: 68%

“…Autophagy-related 16-like 1 (ATG16L1) acts in concert with NODs to regulate antibacterial autophagy. NLR genetic variants are implicated in inflammatory bowel disease, infantile diseases like Blau syndrome, and necrotizing enterocolitis [7,10]. Because twin studies suggest a genetic basis for preterm sepsis, and NLRs mediate immunity to bacteria causing neonatal sepsis, we postulated that single nucleotide polymorphisms (SNPs) in NLRs would alter susceptibility to BSI [11].…”

Section: Introductionmentioning

confidence: 99%

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A Potential Role for the NOD1 Variant (rs6958571) in Gram-Positive Blood Stream Infection in ELBW Infants

Sampath

Mulrooney²,

Patel³

et al. 2017

Neonatology

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Background: The genetic basis of sepsis susceptibility in preterm infants remains understudied. Herein, we investigated the nucleotide binding-oligomerization domain (NOD)-like receptor (NLR) family of immune receptors as putative loci for preterm sepsis susceptibility. Objective: To determine whether single nucleotide polymorphisms (SNPs) in NLR genes are associated with blood stream infections (BSI) in premature infants. Methods: An international cohort of infants with gestational age (GA) <35 weeks were genotyped for SNPs in the ATG16L1, CARD8, NLRP3, NOD2, and NOD1 genes. χ² and logistic regression analyses were used to examine relationships between NLR variants and BSI. Results: Among 764 infants, 138 developed BSI, 113 had gram-positive bacterial (GPB) BSI, and 28 had gram-negative bacterial (GNB) BSI. Infants with BSI had a lower birth weight and GA (p < 0.001), but did not differ in gender, race, or chorioamnionitis. NLR variants were not associated with GPB or GNB BSI in the entire cohort. The CC genotype of the NOD1 SNP (rs6958571) was associated with increased GPB BSI in extremely low birth weight (ELBW, birth weight <1,000 g) infants (OR = 3.3, 95% CI: 1.4-7.5, p = 0.003, n = 362) and in Caucasian infants (OR = 2.5, 95% CI: 1.2-5.4, p = 0.016, n = 535). Regression models adjusting for clinical variables identified ELBW status and the NOD1 CC genotype as risk factors for GPB BSI in Caucasian infants. Conclusions: In this study investigating relationships between NLR variants and sepsis in infants with GA <35 weeks, the NOD1 (rs6958571) SNP was associated with GPB BSI in Caucasian infants and ELBW infants. Replication of our results in an independent cohort would support a role for NLR variants in determining sepsis risk in ELBW infants.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

A Potential Role for the NOD1 Variant (rs6958571) in Gram-Positive Blood Stream Infection in ELBW Infants

Sampath

Mulrooney²,

Patel³

et al. 2017

Neonatology

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“…Because Paneth cells tend to live longer than most other cells of the gut and have many aggregated proteins that could be recycled by other neighboring cells, as damage and stressors to the cells occur, autophagy becomes activated (92). When mutations occur in the autophagy pathway such as in Atg16l1, Paneth cells can become dysfunctional and ultimately trigger intestinal inflammation, which can have implications for gut health such is suggested to be the case with Crohn's disease (92) and NEC (93). Our laboratory has also shown that autophagy may play a role in development of FIGURE 4 | Proposed role of the Paneth cell in development of NEC.…”

Section: Paneth Cells and Mechanisms Of Cellular Deathmentioning

confidence: 99%

The Paneth Cell: The Curator and Defender of the Immature Small Intestine

2020

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Paneth cells were first described in the late 19th century by Gustav Schwalbe and Josef Paneth as columnar epithelial cells possessing prominent eosinophilic granules in their cytoplasm. Decades later there is continued interest in Paneth cells as they play an integral role in maintaining intestinal homeostasis and modulating the physiology of the small intestine and its associated microbial flora. Paneth cells are highly specialized secretory epithelial cells located in the small intestinal crypts of Lieberkühn. The dense granules produced by Paneth cells contain an abundance of antimicrobial peptides and immunomodulating proteins that function to regulate the composition of the intestinal flora. This in turn plays a significant role in secondary regulation of the host microvasculature, the normal injury and repair mechanisms of the intestinal epithelial layer, and the levels of intestinal inflammation. These critical functions may have even more importance in the immature intestine of premature infants. While Paneth cells begin to develop in the middle of human gestation, they do not become immune competent or reach their adult density until closer to term gestation. This leaves preterm infants deficient in normal Paneth cell biology during the greatest window of susceptibility to develop intestinal pathology such as necrotizing enterocolitis (NEC). As 10% of infants worldwide are currently born prematurely, there is a significant population of infants contending with an inadequate cohort of Paneth cells. Infants who have developed NEC have decreased Paneth cell numbers compared to age-matched controls, and ablation of murine Paneth cells results in a NEC-like phenotype suggesting again that Paneth cell function is critical to homeostasis to the immature intestine. This review will provide an up to date and comprehensive look at Paneth cell ontogeny, the impact Paneth cells have on the host-microbial axis in the immature intestine, and the repercussions of Paneth cell dysfunction or loss on injury and repair mechanisms in the immature gut.

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“…Congenital factors include genetic susceptibility and fetal growth restriction, while environmental factors include mechanical ventilation, oxygen exposure, and nutritional deficits. Rare genetic variations may predispose VLBWIs to the development of BPD with systemic complications . In this line, the comorbidity of BPD with neuromuscular dysfunctions may raise the common genetic base of neurological and respiratory development in some tracheostomized VLBWIs.…”

Section: Discussionmentioning

confidence: 99%

“…The pathogenesis of BPD has been known to be associated with both congenital and environmental factors. 28 29,30 In this line, the comorbidity of BPD with neuromuscular dysfunctions may raise the common genetic base of neurological and respiratory development in some tracheostomized VLBWIs. .…”

Section: Causes Of Death After 28 Days Of Lifementioning

confidence: 99%

A nationwide survey on tracheostomy for very‐low‐birth‐weight infants in Japan

Kurata

Ochiai

Inoue

et al. 2018

Pediatric Pulmonology

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Objectives Tracheostomy is indicated for very‐low‐birth‐weight infants (VLBWIs) with prolonged respiratory problems during the perinatal period. The objective of this study is to clarify the epidemiology and risk factors in VLBWIs with tracheostomy after birth in Japan. Methods A total of 40 806 VLBWIs were registered in the Neonatal Research Network of Japan database from 2003 to 2012. Among them, 34 674 infants (85%) survived over 28 days after birth and were subjected to this study. The clinical variables at birth, outcomes at hospital discharge and associated factors for tracheostomy were examined. Results The proportion of VLBWIs with tracheostomy did not increase during the study period (mean 36 cases per year, 0.93%). The rate of in‐hospital death over 28 days after birth did not differ between tracheostomized and non‐tracheostomized infants (2/324, 0.6% vs 314/34 350, 0.9%). Tracheostomized infants more frequently had severe or moderate bronchopulmonary dysplasia (BPD) (75.5% vs 26.0%, P < 0.01) and longer hospitalization (229 days vs 83 days, P < 0.01) than non‐tracheostomized infants. Tracheostomized patients showed higher comorbidities with hypoxic ischemic encephalopathy (odds ratio [OR] 10.98, P < 0.01), muscular disease (OR 10.95, P < 0.01), severe or moderate BPD (OR 7.79, P < 0.01), chromosomal abnormality (OR 4.43, P < 0.01) or sepsis (OR 1.78, P < 0.05) at hospital discharge than non‐tracheostomized patients. Conclusion We demonstrated the non‐increasing rate in tracheostomy for VLBWIs and such cases were associated with an excellent survival in Japan. These data provide evidence that more attentive care must be practiced in order to reduce the pulmonary and neuromuscular burdens of VLBWIs at birth.

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A functional ATG16L1 (T300A) variant is associated with necrotizing enterocolitis in premature infants

Cited by 40 publications

References 42 publications

A Potential Role for the <b><i>NOD1</i></b> Variant <b><i>(</i></b>rs6958571) in Gram-Positive Blood Stream Infection in ELBW Infants

A Potential Role for the <b><i>NOD1</i></b> Variant <b><i>(</i></b>rs6958571) in Gram-Positive Blood Stream Infection in ELBW Infants

The Paneth Cell: The Curator and Defender of the Immature Small Intestine

A nationwide survey on tracheostomy for very‐low‐birth‐weight infants in Japan

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