Genome-wide association study of sepsis in extremely premature infants

Arch Dis Child Fetal Neonatal Ed. 2017 Sep;102(5):F439-F445. doi: 10.1136/archdischild-2016-311545. Epub 2017 Mar 10.

Abstract

Objective: To identify genetic variants associated with sepsis (early-onset 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 anonymised 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 (FDRs) 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 extremely low birthweight infants; however, areas of potential association and pathways meriting further study were identified.

Keywords: ELBW; Genetics; extreme prematurity; infection.

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Adaptor Proteins, Signal Transducing / genetics
  • Cohort Studies
  • Endopeptidases / genetics
  • Female
  • Forkhead Transcription Factors / genetics
  • GTPase-Activating Proteins / genetics
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Infant, Extremely Premature*
  • Infant, Newborn
  • Ion Channels / genetics
  • Male
  • Microfilament Proteins / genetics
  • Polymorphism, Single Nucleotide*
  • Sepsis / genetics*
  • Sepsis / microbiology

Substances

  • ATP-Binding Cassette Transporters
  • Adaptor Proteins, Signal Transducing
  • ELMO1 protein, human
  • FOXL1 protein, human
  • Forkhead Transcription Factors
  • GTPase-Activating Proteins
  • Ion Channels
  • Microfilament Proteins
  • PIEZO2 protein, human
  • RALBP1 protein, human
  • VIL1 protein, human
  • mesenchyme fork head 1 protein
  • Endopeptidases
  • IMMP2L protein, human

Grant support