Lakshmi Srinivasan1, Grier Page2, Haresh Kirpalani1, Jeffrey C Murray3, Abhik Das4, Rosemary D Higgins5, Waldemar A Carlo6, Edward F Bell3, Ronald N Goldberg7, Kurt Schibler8, Beena G Sood9, David K Stevenson10, Barbara J Stoll11, Krisa P Van Meurs10, Karen J Johnson3, Joshua Levy2, Scott A McDonald2, Kristin M Zaterka-Baxter2, Kathleen A Kennedy12, Pablo J Sánchez13, Shahnaz Duara14, Michele C Walsh15, Seetha Shankaran9, James L Wynn16, C Michael Cotten7. 1. Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, Pennsylvania, USA. 2. Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, Research Park, North Carolina, USA. 3. Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA. 4. Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, Maryland, USA. 5. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA. 6. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA. 7. Department of Pediatrics, Duke University, Durham, North Carolina, USA. 8. Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA. 9. Department of Pediatrics, Wayne State University, Detroit, Michigan, USA. 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. Department of Pediatrics, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA. 12. Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas, USA. 13. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 14. University of Miami Miller School of Medicine, Miami, Florida, USA. 15. Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA. 16. Department of Pediatrics, University of Florida, Gainesville, Florida, USA.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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