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Genome-wide association study of sepsis in extremely premature infants
  1. Lakshmi Srinivasan1,
  2. Grier Page2,
  3. Haresh Kirpalani1,
  4. Jeffrey C Murray3,
  5. Abhik Das4,
  6. Rosemary D Higgins5,
  7. Waldemar A Carlo6,
  8. Edward F Bell3,
  9. Ronald N Goldberg7,
  10. Kurt Schibler8,
  11. Beena G Sood9,
  12. David K Stevenson10,
  13. Barbara J Stoll11,
  14. Krisa P Van Meurs10,
  15. Karen J Johnson3,
  16. Joshua Levy2,
  17. Scott A McDonald2,
  18. Kristin M Zaterka-Baxter2,
  19. Kathleen A Kennedy12,
  20. Pablo J Sánchez13,
  21. Shahnaz Duara14,
  22. Michele C Walsh15,
  23. Seetha Shankaran9,
  24. James L Wynn16,
  25. C Michael Cotten7
  26. for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
    1. 1 Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, Pennsylvania, USA
    2. 2 Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, Research Park, North Carolina, USA
    3. 3 Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA
    4. 4 Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, Maryland, USA
    5. 5 Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
    6. 6 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
    7. 7 Department of Pediatrics, Duke University, Durham, North Carolina, USA
    8. 8 Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA
    9. 9 Department of Pediatrics, Wayne State University, Detroit, Michigan, USA
    10. 10 Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California, USA
    11. 11 Department of Pediatrics, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
    12. 12 Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas, USA
    13. 13 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
    14. 14 University of Miami Miller School of Medicine, Miami, Florida, USA
    15. 15 Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA
    16. 16 Department of Pediatrics, University of Florida, Gainesville, Florida, USA
    1. Correspondence to Dr Lakshmi Srinivasan, Department of Pediatrics, The Children's Hospital of Philadelphia, Room 2NW17, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA; srinivasanl{at}


    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.

    • infection
    • ELBW
    • extreme prematurity
    • Genetics

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    • Collaborators We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study: NRN Steering Committee Chair: Alan H. Jobe, MD PhD, University of Cincinnati. Case Western Reserve University, Rainbow Babies & Children's Hospital (U10 HD21364, M01 RR80)—Avroy A. Fanaroff, MD; Nancy S. Newman, RN; Bonnie S. Siner, RN. Cincinnati Children's Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084)—Edward F. Donovan, MD; Vivek Narendran, MD MRCP; Barbara Alexander, RN; Cathy Grisby, BSN CCRC; Jody Hessling, RN; Marcia Worley Mersmann, RN CCRC; Holly L. Mincey, RN BSN. Duke University School of Medicine University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (M01 RR30, U10 HD40492)—Kathy J. Auten, MSHS. Emory University, Children's Healthcare of Atlanta, Grady Memorial Hospital, and Emory Crawford Long Hospital (U10 HD27851, M01 RR39)—Ellen C. Hale, RN BS CCRC. Eunice Kennedy Shriver National Institute of Child Health and Human Development—Linda L. Wright, MD; Sumner J. Yaffe, MD; Elizabeth M. McClure, Med; Stephanie Wilson Archer, MA. RTI International (U10 HD36790)—W. Kenneth Poole, PhD (deceased); Betty K. Hastings; Jeanette O'Donnell Auman, BS. Stanford University, Lucile Packard Children's Hospital (U10 HD27880, M01 RR70)—M. Bethany Ball, BS CCRC. University of Alabama at Birmingham Health System and Children's Hospital of Alabama (U10 HD34216, M01 RR32)—Namasivayam Ambalavanan, MD; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN. University of California—San Diego Medical Center and Sharp Mary Birch Hospital for Women (U10 HD40461)—Neil N. Finer, MD; Maynard R. Rasmussen, MD; David Kaegi, MD; Kathy Arnell, RNC; Clarence Demetrio, RN; Wade Rich, BSHS RRT. University of Iowa (U10 HD53109)—Edward F. Bell, MD. University of Miami Holtz Children's Hospital (U10 HD21397, M01 RR16587)—Charles R. Bauer, MD; Ruth Everett-Thomas, RN MSN. University of Pennsylvania (U10 HD68244)—Barbara Schmidt, MD MSc. University of Tennessee (U10 HD21415)—Sheldon B. Korones, MD (deceased); Henrietta S. Bada, MD; Tina Hudson, RN BSN. University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children's Medical Center Dallas (U10 HD40689, M01 RR633)—Abbot R. Laptook, MD; Walid A. Salhab, MD; Susie Madison, RN; Nancy A. Miller, RN; Gaynelle Hensley, RN; Alicia Guzman. University of Texas Health Science Center at Houston Medical School, Children's Memorial Hermann Hospital, and Lyndon B. Johnson General Hospital (U10 HD21373)—Jon E. Tyson, MD MPH; Kathleen A. Kennedy, MD MPH; Esther G. Akpa, RN BSN; Patty A. Cluff, RN; Claudia I. Franco, RNC MSN; Anna E. Lis, RN BSN; Georgia E. McDavid, RN; Patti Pierce Tate, RCP. Wayne State University, Hutzel Women's Hospital, and Children's Hospital of Michigan (U10 HD21385)—G. Ganesh Konduri, MD; Rebecca Bara, RN BSN; Geraldine Muran, RN BSN.

    • Contributors Participating NRN sites collected data and transmitted it to RTI International, the data coordinating centre (DCC) for the network, which stored, managed and analysed the data for this study. On behalf of the NRN, AD (DCC principal investigator) and GP (DCC statistician) had full access to all of the data in the study, and with the NRN Center Principal Investigators, take responsibility for the integrity of the data and accuracy of the data analysis. LS was responsible for drafting the article and all other authors were involved in revising it critically for important intellectual content. All authors have seen and approved the submission of this version of the manuscript and take responsibility for the entire manuscript.

    • Funding This work was supported by the National Institutes of Health (General Clinical Research Center grants M01 RR30, M01 RR32, M01 RR39, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587, UL1 RR24979) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grants U01 HD36790, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34216, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40689, U10 HD53109, U10 HD68244) provided grant support for the Neonatal Research Network's Genomics Study. In addition, JCM received assistance for the GENEVA study from the National Human Genome Research Institute (U01 HG4423). The funding agencies provided overall oversight for study conduct, but all data analyses and interpretation were independent of the funding agencies.

    • Competing interests None declared.

    • Ethics approval IRBs at all participating sites approved original study; waiver obtained for this analysis as we used deidentified data.

    • Provenance and peer review Not commissioned; externally peer reviewed.