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.
abstract: BACKGROUND
  Acute kidney injury (AKI) is a multifactorial syndrome, but knowledge about its pathophysiology and possible genetic background is limited. Recently the first hypothesis-free genetic association studies have been published to explore individual susceptibility to AKI. We aimed to replicate the previously identified associations between five candidate single nucleotide polymorphisms (SNP) in apoptosis-related genes BCL2, SERPINA4, SERPINA5, and SIK3 and the development of AKI, using a prospective cohort of critically ill patients with sepsis/septic shock, in Finland.
  
  
  METHODS
  This is a prospective, observational multicenter study. Of 2567 patients without chronic kidney disease and with genetic samples included in the Finnish Acute Kidney Injury (FINNAKI) study, 837 patients had sepsis and 627 patients had septic shock. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, considering stages 2 and 3 affected (severe AKI), stage 0 unaffected, and stage 1 indecisive. Genotyping was done using iPLEXTMAssay (Agena Bioscience). The genotyped SNPs were rs8094315 and rs12457893 in the intron of the BCL2 gene, rs2093266 in the SERPINA4 gene, rs1955656 in the SERPINA5 gene and rs625145 in the SIK3 gene. Association analyses were performed using logistic regression with PLINK software.
  
  
  RESULTS
  We found no significant associations between the SNPs and severe AKI in patients with sepsis/septic shock, even after adjustment for confounders. Among patients with septic shock (252 with severe AKI and 226 without AKI (149 with KDIGO stage 1 excluded)), the SNPs rs2093266 and rs1955656 were significantly (odds ratio 0.63, p = 0.04276) associated with stage 2-3 AKI after adjusting for clinical and demographic variables.
  
  
  CONCLUSIONS
  The SNPs rs2093266 in the SERPINA4 and rs1955656 in the SERPINA5 were associated with the development of severe AKI (KDIGO stage 2-3) in critically ill patients with septic shock. For the other SNPs, we did not confirm the previously reported associations.
authors.affiliation: Division of Intensive Care Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. laura.vilander@helsinki.fi.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Vilander
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Mari A
authors.initials: MA
authors.lastname: Kaunisto
authors.affiliation: Division of Intensive Care Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Suvi T
authors.initials: ST
authors.lastname: Vaara
authors.affiliation: Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Ville
authors.initials: V
authors.lastname: Pettilä
mesh_terms: D058186:Acute Kidney Injury / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D000368:Aged; D016638:Critical Illness / Q000453:epidemiology; D005260:Female; D005387:Finland; D014644:Genetic Variation / Q000502:physiology; D006801:Humans; D007362:Intensive Care Units / Q000458:organization & administration; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011446:Prospective Studies; D018046:Protein C Inhibitor / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012189:Retrospective Studies; D015843:Serpins / Q000235:genetics*; D012772:Shock, Septic / Q000150:complications* / Q000503:physiopathology
chemical_list: C000595707:BCL2 protein, human; D018046:Protein C Inhibitor; D019253:Proto-Oncogene Proteins c-bcl-2; C534934:SERPINA5 protein, human; D015843:Serpins; C051324:kallistatin; D011494:Protein Kinases; C509079:SIK3 protein, human
keywords: Acute kidney injury; Apoptosis; BCL2; Genetic susceptibility; SERPINA4; SERPINA5; SIK3; Sepsis; Septic shock