Timothy H Ciesielski1,2, Xueyi Zhang1, Scott M Williams3,4,5, Giorgio Sirugo6,7, Alessandra Tacconelli8, Irja Lutsar9, Vincent Meiffredy de Cabre10, Emmanuel Roilides11, Cinzia Ciccacci12,13, Paola Borgiani12, William K Scott14. 1. The Department of Population and Quantitative Health Sciences at Case Western Reserve University School of Medicine, Cleveland, OH, USA. 2. Mary Ann Swetland Center for Environmental Health at Case Western Reserve University School of Medicine, Cleveland, OH, USA. 3. The Department of Population and Quantitative Health Sciences at Case Western Reserve University School of Medicine, Cleveland, OH, USA. smw154@case.edu. 4. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, USA. smw154@case.edu. 5. 10900 Euclid Ave, Cleveland Institute for Computational Biology, Cleveland, USA. smw154@case.edu. 6. Institute of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. giorgio.sirugo@pennmedicine.upenn.edu. 7. Division of Translational Medicine and Human Genetics, Perelman SPerelman School of Medicine, University of Pennsylvaniachool of Medicine, University of Pennsylvania, Philadelphia, USA. giorgio.sirugo@pennmedicine.upenn.edu. 8. Ospedale San Pietro Fatebenefratelli, Rome, Italy. 9. Department of Microbiology, School of Medicine, University of Tartu, Tartu, Estonia. 10. SC10-US019, INSERM, Villejuif, France. 11. Laboratory of Infectious Diseases, 3rd Department of Paediatrics, School of Medicine, Aristotle University, Thessaloniki, Greece. 12. Dipartimento di Biomedicina e Prevenzione, Facolta' di Medicina e Chirurgia, Universita' di Tor Vergata, Rome, Italy. 13. Unicamillus, Saint Camillus International University of Health Sciences, Rome, Italy. 14. John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Abstract
BACKGROUND: Late-Onset Neonatal Sepsis (LOS) is a rare condition, involving widespread infection, immune disruption, organ dysfunction, and often death. Because exposure to pathogens is not completely preventable, identifying susceptibility factors is critical to characterizing the pathophysiology and developing interventions. Prior studies demonstrated both genetics and infant sex influence susceptibility. Our study was designed to identify LOS associated genetic variants. METHODS: We performed an exploratory genome wide association study (GWAS) with 224 LOS cases and 273 controls from six European countries. LOS was defined as sepsis presenting from 3 to 90 days of age; diagnosis was established by clinical criteria consensus guidelines. We tested for association with both autosomal and X-chromosome variants in the total sample and in sex-stratified analyses. RESULTS: In total, 71 SNPs associated with neonatal sepsis at p < 1 × 10-4 in at least one analysis. Most importantly, sex-stratified analyses revealed associations with multiple SNPs (28 in males and 16 in females), but no variants from single-sex analyses associated with sepsis in the other sex. Pathway analyses showed NOTCH signaling is over-represented among genes linked to these SNPS. CONCLUSION: Our results indicate genetic susceptibility to LOS is sexually dimorphic and corroborate that NOTCH signaling plays a role in determining risk. IMPACT: Genes associate with late onset neonatal sepsis. Notch pathway genes are overrepresented in associations with sepsis. Genes associating with sepsis do not overlap between males and females. Sexual dimorphism can lead to sex specific treatment of sepsis.
BACKGROUND: Late-Onset Neonatal Sepsis (LOS) is a rare condition, involving widespread infection, immune disruption, organ dysfunction, and often death. Because exposure to pathogens is not completely preventable, identifying susceptibility factors is critical to characterizing the pathophysiology and developing interventions. Prior studies demonstrated both genetics and infant sex influence susceptibility. Our study was designed to identify LOS associated genetic variants. METHODS: We performed an exploratory genome wide association study (GWAS) with 224 LOS cases and 273 controls from six European countries. LOS was defined as sepsis presenting from 3 to 90 days of age; diagnosis was established by clinical criteria consensus guidelines. We tested for association with both autosomal and X-chromosome variants in the total sample and in sex-stratified analyses. RESULTS: In total, 71 SNPs associated with neonatal sepsis at p < 1 × 10-4 in at least one analysis. Most importantly, sex-stratified analyses revealed associations with multiple SNPs (28 in males and 16 in females), but no variants from single-sex analyses associated with sepsis in the other sex. Pathway analyses showed NOTCH signaling is over-represented among genes linked to these SNPS. CONCLUSION: Our results indicate genetic susceptibility to LOS is sexually dimorphic and corroborate that NOTCH signaling plays a role in determining risk. IMPACT: Genes associate with late onset neonatal sepsis. Notch pathway genes are overrepresented in associations with sepsis. Genes associating with sepsis do not overlap between males and females. Sexual dimorphism can lead to sex specific treatment of sepsis.
Authors: Anita K M Zaidi; W Charles Huskins; Durrane Thaver; Zulfiqar A Bhutta; Zohair Abbas; Donald A Goldmann Journal: Lancet Date: 2005 Mar 26-Apr 1 Impact factor: 79.321
Authors: Irja Lutsar; Ursula M T Trafojer; Paul T Heath; Tuuli Metsvaht; Joseph Standing; Susanna Esposito; Vincent Meiffredy de Cabre; Clarissa Oeser; Jean-Pierre Aboulker Journal: Trials Date: 2011-09-30 Impact factor: 2.279