Genome-wide association study of sepsis in extremely premature infants

Abstract

Objective To identify genetic variants associated with sepsis (early and late-onset) using a genome wide association (GWA) analysis in a cohort of extremely premature infants. Study Design Previously generated GWA data from the Neonatal Research Network’s anonymized genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole genome amplified DNA was genotyped for 1.2 million single nucleotide polymorphisms (SNPs); 91% of SNPs were successfully genotyped. We imputed 7.2 million additional SNPs. P values and false discovery rates were calculated from multivariate logistic regression analysis adjusting for gender, gestational age and ancestry. Target statistical value was p<10−5. Secondary analyses assessed associations of SNPs with pathogen type. Pathway analyses were also run on primary and secondary end points. Results Data from 757 extremely premature infants were included: 351 infants with sepsis and 406 infants without sepsis. No SNPs reached genome-wide significance levels (5×10−8); two SNPs in proximity to FOXC2 and FOXL1 genes achieved target levels of significance. In secondary analyses, SNPs for ELMO1, IRAK2 (Gram positive sepsis), RALA, IMMP2L (Gram negative sepsis) and PIEZO2 (fungal sepsis) met target significance levels. Pathways associated with sepsis and Gram negative sepsis included gap junctions, fibroblast growth factor receptors, regulators of cell division and Interleukin-1 associated receptor kinase 2 (p values<0.001 and FDR<20%). Conclusions No SNPs met genome-wide significance in this cohort of ELBW infants; however, areas of potential association and pathways meriting further study were identified.

Sepsis and Oxidative Stress in the Newborn: From Pathogenesis to Novel Therapeutic Targets

“…These results were in agreement with a previous study of blood genome-wide expression profile in very low birthweight (VLBW) infants, demonstrating overexpression of genes involved in innate immunity and inflammation in septic patients in comparison to controls [ 76 ]. These aspects could be of major importance in the population of preterm newborns, who exhibited basal overexpression of genes related to inflammation in the gut in comparison to term newborns, as demonstrated by whole genome sequencing of stool-derived mRNA [ 77 ], and overexpressed in septic condition pathways related to IL-1 receptor kinase 2, fibroblast growth factor receptors, gap junctions, and cell division regulators [ 78 ]. Moreover, in a preterm pig model of necrotizing enterocolitis (NEC), the study of intestinal proteomics demonstrated that antibiotic treatment induced several beneficial mucosal pathways, including antioxidant ones, as CAT activity was significantly increased in comparison to untreated animals, suggesting that antibiotic treatment during NEC is associated to a more favorable redox profile, shifting towards antioxidant prevalence [ 79 ].…”

Tumour Necrosis Factor-alpha and Nuclear Factor-kappa B Gene Variants in Sepsis

“…It was detected that various genetic polymorphisms, including TNF-α, IL-1, IL-6, and IL- 10, were associated with a predisposition to infection and increased mortality in patients with sepsis ( 17 , 18 ). In a GWAS study in premature infants, Srinivasan et al ( 19 ) did not report any significant results for common sepsis genes, such as IL-6, TLR-2, TLR-4, etc.…”

Surgical necrotizing enterocolitis in extremely premature neonates is associated with genetic variations in an intergenic region of chromosome 8

“…The same cohort of patients and the same genotyping data used herein was used earlier in GWAS to interrogate potential genetic basis for sepsis ( 32 ), intraventricular hemorrhage ( 23 , 30 ) and bronchopulmonary dysplasia ( 33 ). While all these GWAS identified significant associations between SNPs or SNP clusters with the aforementioned neonatal morbidities, none of those were in the same region of chromosome 8 as the NECRISK region, or in regions on chromosomes 11 and 14 that we found to be associated with NEC.…”