VPS13D Gene Variant Is Associated with Altered IL-6 Production and Mortality in Septic Shock

J Innate Immun. 2015;7(5):545-53. doi: 10.1159/000381265. Epub 2015 Apr 17.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cohort Studies
  • European Continental Ancestry Group / genetics
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • HeLa Cells
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Lymphocyte Activation / genetics
  • Lymphocytes / physiology*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Proteins / genetics*
  • Shock, Septic / genetics*
  • Shock, Septic / immunology
  • Shock, Septic / mortality*
  • Spain
  • Survival Analysis

Substances

  • Interleukin-6
  • Proteins
  • VPS13D protein, human