A functional ATG16L1 (T300A) variant is associated with necrotizing enterocolitis in premature infants.
Sampath Venkatesh,Bhandari Vineet,Berger Jessica,Merchant Daniel,Zhang Liyun,Ladd Mihoko,Menden Heather,Garland Jeffery,Ambalavanan Namasivayam,Mulrooney Neil,Quasney Michael,Dagle John,Lavoie Pascal M,Simpson Pippa,Dahmer Mary
BACKGROUND:The genetic basis of dysfunctional immune responses in necrotizing enterocolitis (NEC) remains unknown. We hypothesized that variants in nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs) and autophagy (ATG) genes modulate vulnerability to NEC. METHODS:We genotyped a multi-center cohort of premature infants with and without NEC for NOD1, NOD2, ATG16L1, CARD8, and NLRP3 variants. Chi-square tests and logistic regression were used for statistical analysis. RESULTS:In our primary cohort (n = 1,015), 86 (8.5%) infants developed NEC. The A allele of the ATG16L1 (Thr300Ala) variant was associated with increased NEC (AA vs. AG vs. GG; 11.3 vs. 8.4 vs. 4.8%, P = 0.009). In regression models for NEC that adjusted for epidemiological confounders, GA (P = 0.033) and the AA genotype (P = 0.038) of ATG16L1 variant were associated with NEC. The association between the A allele of the ATG16L1 variant and NEC remained significant among Caucasian infants (P = 0.02). In a replication cohort (n = 259), NEC rates were highest among infants with the AA genotype but did not reach statistical significance. CONCLUSION:We report a novel association between a hypomorphic variant in an autophagy gene (ATG16L1) and NEC in premature infants. Our data suggest that decreased autophagy arising from genetic variants may confer protection against NEC.
Preventive strategies and factors associated with surgically treated necrotising enterocolitis in extremely preterm infants: an international unit survey linked with retrospective cohort data analysis.
Adams Mark,Bassler Dirk,Darlow Brian A,Lui Kei,Reichman Brian,Hakansson Stellan,Norman Mikael,Lee Shoo K,Helenius Kjell K,Lehtonen Liisa,San Feliciano Laura,Vento Maximo,Moroni Marco,Beltempo Marc,Yang Junmin,Shah Prakesh S,
OBJECTIVES:To compare necrotising enterocolitis (NEC) prevention practices and NEC associated factors between units from eight countries of the International Network for Evaluation of Outcomes of Neonates, and to assess their association with surgical NEC rates. DESIGN:Prospective unit-level survey combined with retrospective cohort study. SETTING:Neonatal intensive care units in Australia/New Zealand, Canada, Finland, Israel, Spain, Sweden, Switzerland and Tuscany (Italy). PATIENTS:Extremely preterm infants born between 24 to 28 weeks' gestation, with birth weights<1500 g, and admitted between 2014-2015. EXPOSURES:NEC prevention practices (probiotics, feeding, donor milk) using responses of an on-line pre-piloted questionnaire containing 10 questions and factors associated with NEC in literature (antenatal steroids, c-section, indomethacin treated patent ductus arteriosus and sepsis) using cohort data. OUTCOME MEASURES:Surgical NEC rates and death following NEC using cohort data. RESULTS:The survey response rate was 91% (153 units). Both probiotic provision and donor milk availability varied between 0%-100% among networks whereas feeding initiation and advancement rates were similar in most networks. The 9792 infants included in the cohort study to link survey results and cohort outcomes, revealed similar baseline characteristics but considerable differences in factors associated with NEC between networks. 397 (4.1%) neonates underwent NEC surgery, ranging from 2.4%-8.4% between networks. Standardised ratios for surgical NEC were lower for Australia/New Zealand, higher for Spain, and comparable for the remaining six networks. CONCLUSIONS:The variation in implementation of NEC prevention practices and in factors associated with NEC in literature could not be associated with the variation in surgical NEC incidence. This corroborates the current lack of consensus surrounding the use of preventive strategies for NEC and emphasises the need for research.