Genome-wide association study of sepsis in extremely premature infants

Lakshmi Srinivasan, Grier Page, Haresh Kirpalani, Jeffrey C. Murray, Abhik Das, Rosemary D. Higgins, Waldemar A. Carlo, Edward F. Bell, Ronald N. Goldberg, Kurt Schibler, Beena G. Sood, David K. Stevenson, Barbara J. Stoll, Krisa P. Van Meurs, Karen J. Johnson, Joshua Levy, Scott A. McDonald, Kristin M. Zaterka-Baxter, Kathleen A. Kennedy, Pablo J. Sánchez & 5 others Shahnaz Duara, Michele C. Walsh, Seetha Shankaran, James L. Wynn, C. Michael Cotten

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 culturepositive 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 (Gramnegative 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.

Original languageEnglish (US)
JournalArchives of Disease in Childhood
DOIs
StateAccepted/In press - Mar 10 2017

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Extremely Premature Infants
Genome-Wide Association Study
Sepsis
Single Nucleotide Polymorphism
Genome
Interleukin-1 Receptor-Associated Kinases
Fibroblast Growth Factor Receptors
Gap Junctions
Meningitis
Cell Division
Gestational Age
Logistic Models
Regression Analysis

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Srinivasan, L., Page, G., Kirpalani, H., Murray, J. C., Das, A., Higgins, R. D., ... Michael Cotten, C. (Accepted/In press). Genome-wide association study of sepsis in extremely premature infants. Archives of Disease in Childhood. https://doi.org/10.1136/archdischild-2016-311545

Genome-wide association study of sepsis in extremely premature infants. / 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.; Michael Cotten, C.

In: Archives of Disease in Childhood, 10.03.2017.

Research output: Contribution to journalArticle

Srinivasan, L, Page, G, Kirpalani, H, Murray, JC, Das, A, Higgins, RD, Carlo, WA, Bell, EF, Goldberg, RN, Schibler, K, Sood, BG, Stevenson, DK, Stoll, BJ, Van Meurs, KP, Johnson, KJ, Levy, J, McDonald, SA, Zaterka-Baxter, KM, Kennedy, KA, Sánchez, PJ, Duara, S, Walsh, MC, Shankaran, S, Wynn, JL & Michael Cotten, C 2017, 'Genome-wide association study of sepsis in extremely premature infants', Archives of Disease in Childhood. https://doi.org/10.1136/archdischild-2016-311545
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. ; Michael Cotten, C. / Genome-wide association study of sepsis in extremely premature infants. In: Archives of Disease in Childhood. 2017.
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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 culturepositive 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 (Gramnegative 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.",
author = "Lakshmi Srinivasan and Grier Page and Haresh Kirpalani and Murray, {Jeffrey C.} and Abhik Das and Higgins, {Rosemary D.} and Carlo, {Waldemar A.} and Bell, {Edward F.} and Goldberg, {Ronald N.} and Kurt Schibler and Sood, {Beena G.} and Stevenson, {David K.} and Stoll, {Barbara J.} and {Van Meurs}, {Krisa P.} and Johnson, {Karen J.} and Joshua Levy and McDonald, {Scott A.} and Zaterka-Baxter, {Kristin M.} and Kennedy, {Kathleen A.} and S{\'a}nchez, {Pablo J.} and Shahnaz Duara and Walsh, {Michele C.} and Seetha Shankaran and Wynn, {James L.} and {Michael Cotten}, C.",
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T1 - Genome-wide association study of sepsis in extremely premature infants

AU - Srinivasan, Lakshmi

AU - Page, Grier

AU - Kirpalani, Haresh

AU - Murray, Jeffrey C.

AU - Das, Abhik

AU - Higgins, Rosemary D.

AU - Carlo, Waldemar A.

AU - Bell, Edward F.

AU - Goldberg, Ronald N.

AU - Schibler, Kurt

AU - Sood, Beena G.

AU - Stevenson, David K.

AU - Stoll, Barbara J.

AU - Van Meurs, Krisa P.

AU - Johnson, Karen J.

AU - Levy, Joshua

AU - McDonald, Scott A.

AU - Zaterka-Baxter, Kristin M.

AU - Kennedy, Kathleen A.

AU - Sánchez, Pablo J.

AU - Duara, Shahnaz

AU - Walsh, Michele C.

AU - Shankaran, Seetha

AU - Wynn, James L.

AU - Michael Cotten, C.

PY - 2017/3/10

Y1 - 2017/3/10

N2 - 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 culturepositive 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 (Gramnegative 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.

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