title: VPS13D Gene Variant Is Associated with Altered IL-6 Production and Mortality in Septic Shock.
abstract: BACKGROUND
  Genetic variations contribute to septic shock mortality. To discover a novel locus, we performed in vitro genome-wide association studies (GWAS) and further tested the result in a cohort of septic shock patients.
  
  
  METHODS
  Two in vitro GWAS using a quantitative trait locus analysis of stimulated IL-6 production in lymphoblastoid cells from 60 individuals of European ancestry were performed. VPS13D rs6685273 was genotyped in European ancestry patients (n = 498). The VPS13D gene was silenced in vitro.
  
  
  RESULTS
  Two GWAS using lymphoblastoid cells identified the locus of VPS13D rs6685273 that was significant in the same direction in both GWAS. The VPS13D rs6685273 C allele was associated with increased IL-6 production. Patients with septic shock who had the VPS13D rs6685273 CC genotype had an increased 28-day mortality (p = 0.023) and more organ failure (p < 0.05) compared to the CT/TT genotypes. VPS13D in vitro gene silencing in the HeLa cell line increased IL-6 production. Furthermore, the rs6685273 genotype was associated with differential VPS13D splice variant expression.
  
  
  CONCLUSIONS
  The VPS13D rs6685273 C allele was associated with increased IL-6 production in vitro. The patients with the VPS13D rs6685273 CC genotype had increased 28-day mortality and increased organ failure. VPS13D appears to regulate IL-6 production.
authors.affiliation: Critical Care Research Laboratories, Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, B.C., Canada.
authors.forename: Taka-aki
authors.initials: TA
authors.lastname: Nakada
authors.forename: John H
authors.initials: JH
authors.lastname: Boyd
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.forename: Rosalía
authors.initials: R
authors.lastname: Aguirre-Hernández
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wilkinson
authors.forename: Simone A
authors.initials: SA
authors.lastname: Thair
authors.forename: Emiri
authors.initials: E
authors.lastname: Nakada
authors.forename: Melissa K
authors.initials: MK
authors.lastname: McConechy
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Fjell
authors.forename: Keith R
authors.initials: KR
authors.lastname: Walley
mesh_terms: D000368:Aged; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D008214:Lymphocytes / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012772:Shock, Septic / Q000235:genetics* / Q000276:immunology / Q000401:mortality*; D013030:Spain; D016019:Survival Analysis; D044465:White People / Q000235:genetics
chemical_list: D015850:Interleukin-6; D011506:Proteins; C495325:VPS13D protein, human