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

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

Author information

1
Critical Care Research Laboratories, Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, B.C., Canada.

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.

PMID:
25896417
DOI:
10.1159/000381265
[Indexed for MEDLINE]
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