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

作者：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

来源：Pediatric Research, 2017, 81(4): 582-588.

DOI：10.1038/pr.2016.260

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 (Thr300A1a) 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 dedeased autophagy arising from genetic variants may confer protection against NEC.

• 出版日期2017-4