Genome-wide association study of sepsis in extremely premature infants. Issue 5 (10th March 2017)

• Record Type: Journal Article
• Authors: Srinivasan, Lakshmi; Page, Grier; Kirpalani, Haresh; Murray, Jeffrey C; Das, Abhik; Higgins, Rosemary D; Carlo, Waldemar A; Bell, Edward F; Goldberg, Ronald N; Schibler, Kurt; Sood, Beena G; Stevenson, David K; Stoll, Barbara J; Van Meurs, Krisa P; Johnson, Karen J; Levy, Joshua; McDonald, Scott A; Zaterka-Baxter, Kristin M; Kennedy, Kathleen A; Sánchez, Pablo J; Duara, Shahnaz; Walsh, Michele C; Shankaran, Seetha; Wynn, James L; Cotten, C Michael
• Other Names: author non-byline.; Jobe Alan H. author non-byline.; Fanaroff Avroy A. author non-byline.; Newman Nancy S. author non-byline.; Siner Bonnie S. author non-byline.; Donovan Edward F. author non-byline.; Narendran Vivek author non-byline.; Alexander Barbara author non-byline.; Grisby Cathy author non-byline.; Hessling Jody author non-byline.; Mincey Holly L. author non-byline.; Auten Kathy J. author non-byline.; Hale Ellen C. author non-byline.; Wright Linda L. author non-byline.; Yaffe Sumner J. author non-byline.; McClure Elizabeth M. author non-byline.; Archer Stephanie Wilson author non-byline.; Poole W. Kenneth author non-byline.; Hastings Betty K. author non-byline.; Auman Jeanette O'Donnell author non-byline.; Ball M. Bethany author non-byline.; Ambalavanan Namasivayam author non-byline.; Collins Monica V. author non-byline.; Cosby Shirley S. author non-byline.; Finer Neil N. author non-byline.; Rasmussen Maynard R. author non-byline.; Kaegi David author non-byline.; Arnell Kathy author non-byline.; Demetrio Clarence author non-byline.; Rich Wade author non-byline.; Bell Edward F. author non-byline.; Bauer Charles R. author non-byline.; Everett-Thomas Ruth author non-byline.; Schmidt Barbara author non-byline.; Korones Sheldon B. author non-byline.; Bada Henrietta S. author non-byline.; Hudson Tina author non-byline.; Laptook Abbot R. author non-byline.; Salhab Walid A. author non-byline.; Madison Susie author non-byline.; Miller Nancy A. author non-byline.; Hensley Gaynelle author non-byline.; Guzman Alicia author non-byline.; Tyson Jon E. author non-byline.; Kennedy Kathleen A. author non-byline.; Akpa Esther G. author non-byline.; Cluff Patty A. author non-byline.; Franco Claudia I. author non-byline.; Lis Anna E. author non-byline.; McDavid Georgia E. author non-byline.; Tate Patti Pierce author non-byline.; Konduri G. Ganesh author non-byline.; Bara Rebecca author non-byline.; Muran Geraldine author non-byline.;
• Is Part Of: Archives of disease in childhood. Volume 102:Issue 5(2017)
• Page Start: F439
• Page End: F445
• Publication Date: 2017-03-10
• Subjects: infection -- ELBW -- extreme prematurity -- Genetics; Infants -- Diseases -- Periodicals; Newborn infants -- Diseases -- Periodicals; Fetus -- Diseases -- Periodicals; 618.920105
• DOI: 10.1136/archdischild-2016-311545
• Languages: English
• ISSNs: 1359-2998

Abstract

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.