{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:59:45Z","timestamp":1787065185221,"version":"build-2736575974"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T00:00:00Z","timestamp":1733356800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["1 K08 DK131346-03"],"award-info":[{"award-number":["1 K08 DK131346-03"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005831","name":"Foundation for Anesthesia Education and Research","doi-asserted-by":"publisher","award":["Mentored Research Training Grant (MRTG)"],"award-info":[{"award-number":["Mentored Research Training Grant (MRTG)"]}],"id":[{"id":"10.13039\/100005831","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000092","name":"U.S. National Library of Medicine","doi-asserted-by":"publisher","award":["R01- LM010685-11"],"award-info":[{"award-number":["R01- LM010685-11"]}],"id":[{"id":"10.13039\/100000092","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["K23 HL148640"],"award-info":[{"award-number":["K23 HL148640"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"\n Background<\/jats:title>\n Kidney dysfunction is a common complication in septic patients. Studies have identified numerous risk factors for sepsis-associated acute kidney injury (S-AKI), yet there is wide variability in the incidence even among patients with similar risk factors, suggesting the presence of additional uncharacterized risk factors, including genetic differences. The expansion of biobanks, advances in genotyping, and standardized diagnostic criteria have enabled large-scale, hypothesis-generating studies into the genetic mechanisms underlying S-AKI. We hypothesize that the genetic pathway behind S-AKI has overlapping mechanisms with key differences based upon the specific subtype of acute kidney injury (AKI).<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n To test this hypothesis, we performed a genome-wide association study (GWAS) of S-AKI in three logistic regression models. Model 1, controlled for 1) age, 2) sex, 3) genotyping chip, and 4) the first five principal components. In Model 2, pre-sepsis baseline serum creatinine was added to the variables in Model 1. Finally, in Model 3, we controlled for the full range of patient, clinical, and ICU-related risk factors. Each of the 3-models were repeated in a pre-specified sensitivity analysis of higher severity S-AKI, defined as KDIGO Stage 2 or 3. We then compare associated variants and genes from our GWAS with previously published AKI sub-types and model other factors associated with S-AKI in our dataset.<\/jats:p>\n <\/jats:sec>\n \n Findings<\/jats:title>\n \n 3,348 qualifying Sepsis-3 patients have been genotyped in our dataset. Of these patients, 383 (11.4%) developed Stage 1, 2, or 3 AKI (primary outcome) and 181 (5.4%) developed Stage 2 or 3 AKI (sensitivity analysis). The median age was 61 years (interquartile range (IQR): 51,69), 42% were female, and the increase in SOFA score (between 48-hours before to 24-hours after the onset of suspected infection) was 2 (2\u20133). No variants exceeded our threshold for genome-wide significance (\n P<\/jats:italic>\n <5x10\n -8<\/jats:sup>\n ), however, a total of 13 variants exceeded the suggestive (\n P<\/jats:italic>\n <1x10\n -6<\/jats:sup>\n ) threshold. Notably,\n rs184516290<\/jats:bold>\n (chr1:199814965:G:A), near the\n \n NR5A2<\/jats:italic>\n <\/jats:bold>\n gene, chr1:199805801:T:TA, also near the\n \n NR5A2<\/jats:italic>\n <\/jats:bold>\n gene, and\n rs117313146<\/jats:bold>\n (chr15:31999784:G:C), near the\n \n CHRNA7<\/jats:italic>\n <\/jats:bold>\n gene, were associated with S-AKI at the suggestive level in all three models presented. Variants in the suppressor of fused homolog (\n \n SUFU<\/jats:italic>\n <\/jats:bold>\n ) gene, previously shown to be correlated with renal function in bacteremic patients, consistently exceeded the\n P<\/jats:italic>\n <0.05 threshold in our models.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n While failing to identify any novel association for S-AKI at the level of genome-wide significance, our study did suggest multiple variants in previously characterized pathways for S-AKI including\n \n CHRNA7<\/jats:italic>\n ,\n NR5A2<\/jats:italic>\n ,\n <\/jats:bold>\n and\n \n SUFU<\/jats:italic>\n <\/jats:bold>\n . We failed to replicate associations from multiple prior studies which may result from differences in how the phenotype was defined or, alternatively, limited genetic contribution and low heritability.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1371\/journal.pone.0311318","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T13:26:52Z","timestamp":1733405212000},"page":"e0311318","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genetic variants associated with sepsis-associated acute kidney injury"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0997-6272","authenticated-orcid":true,"given":"Nicholas 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D.","family":"Kertai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milo C.","family":"Engoren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,12,5]]},"reference":[{"key":"pone.0311318.ref001","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"M Singer","year":"2016","journal-title":"JAMA"},{"key":"pone.0311318.ref002","doi-asserted-by":"crossref","first-page":"4","DOI":"10.4161\/viru.27372","article-title":"Epidemiology of severe sepsis","volume":"5","author":"FB Mayr","year":"2014","journal-title":"Virulence"},{"key":"pone.0311318.ref003","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1111\/aas.12133","article-title":"Acute kidney injury in patients with severe 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Nephrol"},{"key":"pone.0311318.ref013","doi-asserted-by":"crossref","first-page":"154150","DOI":"10.1016\/j.jcrc.2022.154150","article-title":"Factors associated with occurrence and severity of acute kidney injury in patients with Sepsis\u2014A retrospective database study","volume":"72","author":"AW Carter","year":"2022","journal-title":"J Crit Care"},{"key":"pone.0311318.ref014","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1097\/CCM.0b013e3182514bca","article-title":"BCL2 genetic variants are associated with acute kidney injury in septic shock*","volume":"40","author":"AJ Frank","year":"2012","journal-title":"Crit Care Med"},{"key":"pone.0311318.ref015","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jcrc.2017.11.019","article-title":"Genetic variants and acute kidney injury: A review of the literature","volume":"44","author":"DB Larach","year":"2018","journal-title":"J Crit 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Med"},{"key":"pone.0311318.ref019","doi-asserted-by":"crossref","first-page":"c179","DOI":"10.1159\/000339789","article-title":"KDIGO clinical practice guidelines for acute kidney injury","volume":"120","author":"A. Khwaja","year":"2012","journal-title":"Nephron Clin Pract"},{"key":"pone.0311318.ref020","doi-asserted-by":"crossref","first-page":"e0265052","DOI":"10.1371\/journal.pone.0265052","article-title":"Genetic variants associated with sepsis","volume":"17","author":"M Engoren","year":"2022","journal-title":"PLoS One"},{"key":"pone.0311318.ref021","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/gepi.20410","article-title":"STrengthening the REporting of Genetic Association Studies (STREGA)\u2014an extension of the STROBE statement","volume":"33","author":"J Little","year":"2009","journal-title":"Genet Epidemiol"},{"key":"pone.0311318.ref022","doi-asserted-by":"crossref","first-page":"358","DOI":"10.4037\/ajcc2023299","article-title":"Factors Associated With Initiation of Mechanical Ventilation in Patients With Sepsis: Retrospective Observational Study","volume":"32","author":"RE Freundlich","year":"2023","journal-title":"Am J Crit Care"},{"key":"pone.0311318.ref023","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1056\/NEJMoa1704154","article-title":"Angiotensin II for the Treatment of Vasodilatory Shock","volume":"377","author":"A Khanna","year":"2017","journal-title":"N Engl J Med"},{"key":"pone.0311318.ref024","doi-asserted-by":"crossref","first-page":"e1008500","DOI":"10.1371\/journal.pgen.1008500","article-title":"Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic\/Latino populations","volume":"15","author":"MH Kowalski","year":"2019","journal-title":"PLoS Genet"},{"key":"pone.0311318.ref025","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1097\/01.mlr.0000182534.19832.83","article-title":"Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data","volume":"43","author":"H Quan","year":"2005","journal-title":"Med Care"},{"key":"pone.0311318.ref026","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1038\/s41588-018-0184-y","article-title":"Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies","volume":"50","author":"W Zhou","year":"2018","journal-title":"Nat Genet"},{"key":"pone.0311318.ref027","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1186\/1471-2164-9-516","article-title":"Establishing an adjusted p-value threshold to control the family-wide type 1 error in genome wide association studies","volume":"9","author":"P Duggal","year":"2008","journal-title":"BMC Genomics"},{"key":"pone.0311318.ref028","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"K Watanabe","year":"2017","journal-title":"Nat Commun"},{"key":"pone.0311318.ref029","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1111\/j.0006-341X.1999.00997.x","article-title":"Genomic control for association studies","volume":"55","author":"B Devlin","year":"1999","journal-title":"Biometrics"},{"key":"pone.0311318.ref030","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/ng.2653","article-title":"The Genotype-Tissue Expression (GTEx) project","volume":"45","author":"GTEx Consortium","year":"2013","journal-title":"Nat Genet"},{"key":"pone.0311318.ref031","doi-asserted-by":"crossref","DOI":"10.1093\/g3journal\/jkaa056","article-title":"Revisiting the genome-wide significance threshold for common variant GWAS","volume":"11","author":"Z Chen","year":"2021","journal-title":"G3"},{"key":"pone.0311318.ref032","doi-asserted-by":"crossref","first-page":"e35361","DOI":"10.1371\/journal.pone.0035361","article-title":"Nicotinic acetylcholine receptor agonists attenuate septic acute kidney injury in mice by suppressing inflammation and proteasome activity","volume":"7","author":"PK Chatterjee","year":"2012","journal-title":"PLoS One"},{"key":"pone.0311318.ref033","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-018-0061-x","article-title":"The proximal tubular \u03b17 nicotinic acetylcholine receptor attenuates ischemic acute kidney injury through Akt\/PKC signaling-mediated HO-1 induction","volume":"50","author":"H Kim","year":"2018","journal-title":"Exp Mol Med"},{"key":"pone.0311318.ref034","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1002\/eji.201040540","article-title":"Unphosphorylated STAT3 modulates alpha 7 nicotinic receptor signaling and cytokine production in sepsis","volume":"40","author":"G Pe\u00f1a","year":"2010","journal-title":"Eur J Immunol"},{"key":"pone.0311318.ref035","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/nature01339","article-title":"Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation","volume":"421","author":"H Wang","year":"2003","journal-title":"Nature"},{"key":"pone.0311318.ref036","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1038\/nm1124","article-title":"Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis","volume":"10","author":"H Wang","year":"2004","journal-title":"Nat Med"},{"key":"pone.0311318.ref037","article-title":"Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by DNA minor groove anchor competition","author":"W Kobayashi","year":"2024","journal-title":"Nat Struct Mol Biol"},{"key":"pone.0311318.ref038","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1016\/j.bbadis.2016.06.013","article-title":"Nuclear receptor NR5A2 is involved in the calreticulin gene regulation during renal fibrosis","volume":"1862","author":"E Arvaniti","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"pone.0311318.ref039","doi-asserted-by":"crossref","first-page":"5949","DOI":"10.1111\/jcmm.17627","article-title":"Calreticulin in renal fibrosis: A short review","volume":"26","author":"PK Politis","year":"2022","journal-title":"J Cell Mol Med"},{"key":"pone.0311318.ref040","doi-asserted-by":"crossref","first-page":"8155","DOI":"10.1007\/s11033-021-06784-1","article-title":"Nuclear receptor subfamily 5 group A member 2 (NR5A2): role in health and diseases","volume":"48","author":"N Sandhu","year":"2021","journal-title":"Mol Biol Rep"},{"key":"pone.0311318.ref041","doi-asserted-by":"crossref","first-page":"113513","DOI":"10.1016\/j.celrep.2023.113513","article-title":"Liver receptor homolog-1 (NR5A2) orchestrates hepatic inflammation and TNF-induced cell death","volume":"42","author":"R Lambrecht","year":"2023","journal-title":"Cell Rep"},{"key":"pone.0311318.ref042","first-page":"34","article-title":"Gene expression profiling of sepsis-associated acute kidney injury","volume":"20","author":"J-J Yang","year":"2020","journal-title":"Exp Ther Med"},{"key":"pone.0311318.ref043","doi-asserted-by":"crossref","first-page":"112420","DOI":"10.1016\/j.intimp.2024.112420","article-title":"Unraveling the genetic and molecular landscape of sepsis and acute kidney injury: A comprehensive GWAS and machine learning approach","volume":"137","author":"S Yang","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"pone.0311318.ref044","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s41065-021-00176-y","article-title":"Bioinformatic analysis identifies potential biomarkers and therapeutic targets of septic-shock-associated acute kidney injury","volume":"158","author":"Y Tang","year":"2021","journal-title":"Hereditas"},{"key":"pone.0311318.ref045","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.meegid.2013.03.025","article-title":"Polymorphisms in the SUFU gene are associated with organ injury protection and sepsis severity in patients with Enterobacteriacea bacteremia","volume":"16","author":"AF Henao-Mart\u00ednez","year":"2013","journal-title":"Infect Genet Evol"},{"key":"pone.0311318.ref046","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.jcrc.2012.11.010","article-title":"Genetic predisposition to acute kidney injury induced by severe sepsis","volume":"28","author":"P Cardinal-Fern\u00e1ndez","year":"2013","journal-title":"J Crit Care"},{"key":"pone.0311318.ref047","doi-asserted-by":"crossref","first-page":"e35838","DOI":"10.1371\/journal.pone.0035838","article-title":"A multicentre study of acute kidney injury in severe sepsis and septic shock: association with inflammatory phenotype and HLA genotype","volume":"7","author":"D Payen","year":"2012","journal-title":"PLoS One"},{"key":"pone.0311318.ref048","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s13054-017-1631-3","article-title":"Genetic variants in SERPINA4 and SERPINA5, but not BCL2 and SIK3 are associated with acute kidney injury in critically ill patients with septic shock","volume":"21","author":"FINNAKI study group","year":"2017","journal-title":"Crit Care"},{"key":"pone.0311318.ref049","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1213\/ANE.0000000000001323","article-title":"Acute Kidney Injury After Abdominal Surgery: Incidence, Risk Factors, and Outcome","volume":"122","author":"TE Long","year":"2016","journal-title":"Anesth Analg"},{"key":"pone.0311318.ref050","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/j.jvs.2016.04.009","article-title":"Renal dysfunction and the associated decrease in survival after elective endovascular aneurysm repair","volume":"64","author":"DS Zarkowsky","year":"2016","journal-title":"J Vasc Surg"},{"key":"pone.0311318.ref051","doi-asserted-by":"crossref","first-page":"e2133094","DOI":"10.1001\/jamanetworkopen.2021.33094","article-title":"Association of Oliguria With Acute Kidney Injury Diagnosis, Severity 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Global Biobank Meta-analysis Initiative: Powering genetic discovery across human diseases. 69th Annual Meeting of the American Society of Human Genetics. 2019."}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0311318","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T13:27:08Z","timestamp":1733405228000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0311318"}},"subtitle":[],"editor":[{"given":"Tarek Samy","family":"Abdelaziz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,12,5]]},"references-count":52,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0311318","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,5]]}}}