Late-onset neonatal sepsis: genetic differences by sex and involvement of the NOTCH pathway
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 an...
Gespeichert in:
| Veröffentlicht in: | Pediatric research 2023-03, Vol.93 (4), p.1085-1095 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1095 |
|---|---|
| container_issue | 4 |
| container_start_page | 1085 |
| container_title | Pediatric research |
| container_volume | 93 |
| creator | Ciesielski, Timothy H. Zhang, Xueyi Tacconelli, Alessandra Lutsar, Irja de Cabre, Vincent Meiffredy Roilides, Emmanuel Ciccacci, Cinzia Borgiani, Paola Scott, William K. Williams, Scott M. Sirugo, Giorgio |
| description | 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
|
| doi_str_mv | 10.1038/s41390-022-02114-8 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2789591034</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2789591034</sourcerecordid><originalsourceid>FETCH-LOGICAL-c375t-fd6c2d3fab34b240e037844eaf375a0557e205142b5207d523ea8c69229c0ff53</originalsourceid><addsrcrecordid>eNp9kE1LAzEQhoMotn78AQ8S8Lyaz27WmxS_oNiLnjyE7O6k3dJm1ySt9t8b3ao3YYaBed95Bx6Ezii5pISrqyAoL0hGGEtNqcjUHhpSydNKiHwfDQnhNONFoQboKIQFIVRIJQ7RgEuVSqghep2YCFnrAkTsoHUmmiUO0IUmXOMZOIhNhevGWvDgKgi43Cb5AxtX48Zt2uUGVuAibi2Oc8BP0-fxA-5MnL-b7Qk6sGYZ4HQ3j9HL3W3Ss8n0_nF8M8kqnsuY2XpUsZpbU3JRMkGA8FwJAcYm2RApc2BEUsFKyUheS8bBqGpUMFZUxFrJj9FFn9v59m0NIepFu_YuvdQsV4UsEi2RXKx3Vb4NwYPVnW9Wxm81JfqLp-556sRTf_PUKh2d76LX5Qrq35MfgMnAe0NIkpuB__v9T-wn185_mg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2789591034</pqid></control><display><type>article</type><title>Late-onset neonatal sepsis: genetic differences by sex and involvement of the NOTCH pathway</title><source>MEDLINE</source><source>SpringerLink Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Ciesielski, Timothy H. ; Zhang, Xueyi ; Tacconelli, Alessandra ; Lutsar, Irja ; de Cabre, Vincent Meiffredy ; Roilides, Emmanuel ; Ciccacci, Cinzia ; Borgiani, Paola ; Scott, William K. ; Williams, Scott M. ; Sirugo, Giorgio</creator><creatorcontrib>Ciesielski, Timothy H. ; Zhang, Xueyi ; Tacconelli, Alessandra ; Lutsar, Irja ; de Cabre, Vincent Meiffredy ; Roilides, Emmanuel ; Ciccacci, Cinzia ; Borgiani, Paola ; Scott, William K. ; Williams, Scott M. ; Sirugo, Giorgio ; NeoMero Consortium</creatorcontrib><description>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.</description><identifier>ISSN: 0031-3998</identifier><identifier>EISSN: 1530-0447</identifier><identifier>DOI: 10.1038/s41390-022-02114-8</identifier><identifier>PMID: 35835848</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Europe ; Female ; Genome-Wide Association Study ; Humans ; Infant ; Infant, Newborn ; Male ; Medicine ; Medicine & Public Health ; Neonatal Sepsis - genetics ; Pediatric Surgery ; Pediatrics ; Population Study Article ; Sepsis ; Sepsis - genetics ; Sex Characteristics</subject><ispartof>Pediatric research, 2023-03, Vol.93 (4), p.1085-1095</ispartof><rights>The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc 2022</rights><rights>2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.</rights><rights>The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc 2022.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-fd6c2d3fab34b240e037844eaf375a0557e205142b5207d523ea8c69229c0ff53</citedby><cites>FETCH-LOGICAL-c375t-fd6c2d3fab34b240e037844eaf375a0557e205142b5207d523ea8c69229c0ff53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41390-022-02114-8$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41390-022-02114-8$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35835848$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ciesielski, Timothy H.</creatorcontrib><creatorcontrib>Zhang, Xueyi</creatorcontrib><creatorcontrib>Tacconelli, Alessandra</creatorcontrib><creatorcontrib>Lutsar, Irja</creatorcontrib><creatorcontrib>de Cabre, Vincent Meiffredy</creatorcontrib><creatorcontrib>Roilides, Emmanuel</creatorcontrib><creatorcontrib>Ciccacci, Cinzia</creatorcontrib><creatorcontrib>Borgiani, Paola</creatorcontrib><creatorcontrib>Scott, William K.</creatorcontrib><creatorcontrib>Williams, Scott M.</creatorcontrib><creatorcontrib>Sirugo, Giorgio</creatorcontrib><creatorcontrib>NeoMero Consortium</creatorcontrib><title>Late-onset neonatal sepsis: genetic differences by sex and involvement of the NOTCH pathway</title><title>Pediatric research</title><addtitle>Pediatr Res</addtitle><addtitle>Pediatr Res</addtitle><description>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.</description><subject>Europe</subject><subject>Female</subject><subject>Genome-Wide Association Study</subject><subject>Humans</subject><subject>Infant</subject><subject>Infant, Newborn</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Neonatal Sepsis - genetics</subject><subject>Pediatric Surgery</subject><subject>Pediatrics</subject><subject>Population Study Article</subject><subject>Sepsis</subject><subject>Sepsis - genetics</subject><subject>Sex Characteristics</subject><issn>0031-3998</issn><issn>1530-0447</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kE1LAzEQhoMotn78AQ8S8Lyaz27WmxS_oNiLnjyE7O6k3dJm1ySt9t8b3ao3YYaBed95Bx6Ezii5pISrqyAoL0hGGEtNqcjUHhpSydNKiHwfDQnhNONFoQboKIQFIVRIJQ7RgEuVSqghep2YCFnrAkTsoHUmmiUO0IUmXOMZOIhNhevGWvDgKgi43Cb5AxtX48Zt2uUGVuAibi2Oc8BP0-fxA-5MnL-b7Qk6sGYZ4HQ3j9HL3W3Ss8n0_nF8M8kqnsuY2XpUsZpbU3JRMkGA8FwJAcYm2RApc2BEUsFKyUheS8bBqGpUMFZUxFrJj9FFn9v59m0NIepFu_YuvdQsV4UsEi2RXKx3Vb4NwYPVnW9Wxm81JfqLp-556sRTf_PUKh2d76LX5Qrq35MfgMnAe0NIkpuB__v9T-wn185_mg</recordid><startdate>20230301</startdate><enddate>20230301</enddate><creator>Ciesielski, Timothy H.</creator><creator>Zhang, Xueyi</creator><creator>Tacconelli, Alessandra</creator><creator>Lutsar, Irja</creator><creator>de Cabre, Vincent Meiffredy</creator><creator>Roilides, Emmanuel</creator><creator>Ciccacci, Cinzia</creator><creator>Borgiani, Paola</creator><creator>Scott, William K.</creator><creator>Williams, Scott M.</creator><creator>Sirugo, Giorgio</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20230301</creationdate><title>Late-onset neonatal sepsis: genetic differences by sex and involvement of the NOTCH pathway</title><author>Ciesielski, Timothy H. ; Zhang, Xueyi ; Tacconelli, Alessandra ; Lutsar, Irja ; de Cabre, Vincent Meiffredy ; Roilides, Emmanuel ; Ciccacci, Cinzia ; Borgiani, Paola ; Scott, William K. ; Williams, Scott M. ; Sirugo, Giorgio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-fd6c2d3fab34b240e037844eaf375a0557e205142b5207d523ea8c69229c0ff53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Europe</topic><topic>Female</topic><topic>Genome-Wide Association Study</topic><topic>Humans</topic><topic>Infant</topic><topic>Infant, Newborn</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Neonatal Sepsis - genetics</topic><topic>Pediatric Surgery</topic><topic>Pediatrics</topic><topic>Population Study Article</topic><topic>Sepsis</topic><topic>Sepsis - genetics</topic><topic>Sex Characteristics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ciesielski, Timothy H.</creatorcontrib><creatorcontrib>Zhang, Xueyi</creatorcontrib><creatorcontrib>Tacconelli, Alessandra</creatorcontrib><creatorcontrib>Lutsar, Irja</creatorcontrib><creatorcontrib>de Cabre, Vincent Meiffredy</creatorcontrib><creatorcontrib>Roilides, Emmanuel</creatorcontrib><creatorcontrib>Ciccacci, Cinzia</creatorcontrib><creatorcontrib>Borgiani, Paola</creatorcontrib><creatorcontrib>Scott, William K.</creatorcontrib><creatorcontrib>Williams, Scott M.</creatorcontrib><creatorcontrib>Sirugo, Giorgio</creatorcontrib><creatorcontrib>NeoMero Consortium</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Pediatric research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ciesielski, Timothy H.</au><au>Zhang, Xueyi</au><au>Tacconelli, Alessandra</au><au>Lutsar, Irja</au><au>de Cabre, Vincent Meiffredy</au><au>Roilides, Emmanuel</au><au>Ciccacci, Cinzia</au><au>Borgiani, Paola</au><au>Scott, William K.</au><au>Williams, Scott M.</au><au>Sirugo, Giorgio</au><aucorp>NeoMero Consortium</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Late-onset neonatal sepsis: genetic differences by sex and involvement of the NOTCH pathway</atitle><jtitle>Pediatric research</jtitle><stitle>Pediatr Res</stitle><addtitle>Pediatr Res</addtitle><date>2023-03-01</date><risdate>2023</risdate><volume>93</volume><issue>4</issue><spage>1085</spage><epage>1095</epage><pages>1085-1095</pages><issn>0031-3998</issn><eissn>1530-0447</eissn><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.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>35835848</pmid><doi>10.1038/s41390-022-02114-8</doi><tpages>11</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0031-3998 |
| ispartof | Pediatric research, 2023-03, Vol.93 (4), p.1085-1095 |
| issn | 0031-3998 1530-0447 |
| language | eng |
| recordid | cdi_proquest_journals_2789591034 |
| source | MEDLINE; SpringerLink Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Europe Female Genome-Wide Association Study Humans Infant Infant, Newborn Male Medicine Medicine & Public Health Neonatal Sepsis - genetics Pediatric Surgery Pediatrics Population Study Article Sepsis Sepsis - genetics Sex Characteristics |
| title | Late-onset neonatal sepsis: genetic differences by sex and involvement of the NOTCH pathway |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T08%3A07%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Late-onset%20neonatal%20sepsis:%20genetic%20differences%20by%20sex%20and%20involvement%20of%20the%20NOTCH%20pathway&rft.jtitle=Pediatric%20research&rft.au=Ciesielski,%20Timothy%20H.&rft.aucorp=NeoMero%20Consortium&rft.date=2023-03-01&rft.volume=93&rft.issue=4&rft.spage=1085&rft.epage=1095&rft.pages=1085-1095&rft.issn=0031-3998&rft.eissn=1530-0447&rft_id=info:doi/10.1038/s41390-022-02114-8&rft_dat=%3Cproquest_cross%3E2789591034%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2789591034&rft_id=info:pmid/35835848&rfr_iscdi=true |