title: Genome-wide association study of sepsis in extremely premature infants.
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.
  
  
  METHODS
  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.
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Srinivasan
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, Research Park, North Carolina, USA.
authors.forename: Grier
authors.initials: G
authors.lastname: Page
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Haresh
authors.initials: H
authors.lastname: Kirpalani
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, Maryland, USA.
authors.forename: Abhik
authors.initials: A
authors.lastname: Das
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Rosemary D
authors.initials: RD
authors.lastname: Higgins
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Waldemar A
authors.initials: WA
authors.lastname: Carlo
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Bell
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina, USA.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Goldberg
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Schibler
authors.affiliation: Department of Pediatrics, Wayne State University, Detroit, Michigan, USA.
authors.forename: Beena G
authors.initials: BG
authors.lastname: Sood
authors.affiliation: Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Stevenson
authors.affiliation: Department of Pediatrics, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Stoll
authors.affiliation: Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California, USA.
authors.forename: Krisa P
authors.initials: KP
authors.lastname: Van Meurs
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Johnson
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, Research Park, North Carolina, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Levy
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, Research Park, North Carolina, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: McDonald
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, Research Park, North Carolina, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Zaterka-Baxter
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Kennedy
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Sánchez
authors.affiliation: University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Duara
authors.affiliation: Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Michele C
authors.initials: MC
authors.lastname: Walsh
authors.affiliation: Department of Pediatrics, Wayne State University, Detroit, Michigan, USA.
authors.forename: Seetha
authors.initials: S
authors.lastname: Shankaran
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida, USA.
authors.forename: James L
authors.identifier: http://orcid.org/0000-0001-7052-4836
authors.initials: JL
authors.lastname: Wynn
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina, USA.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Cotten
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D015331:Cohort Studies; D010450:Endopeptidases / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D007473:Ion Channels / Q000235:genetics; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018805:Sepsis / Q000235:genetics* / Q000382:microbiology
chemical_list: D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; C465214:ELMO1 protein, human; C491001:FOXL1 protein, human; D051858:Forkhead Transcription Factors; D020690:GTPase-Activating Proteins; D007473:Ion Channels; D008840:Microfilament Proteins; C000589132:PIEZO2 protein, human; C095637:RALBP1 protein, human; C569754:VIL1 protein, human; C082078:mesenchyme fork head 1 protein; D010450:Endopeptidases; C425070:IMMP2L protein, human
keywords: ELBW; Genetics; extreme prematurity; infection