VPS13D gene variant is associated with altered IL-6 production and mortality in septic shock

TitleVPS13D gene variant is associated with altered IL-6 production and mortality in septic shock
Publication TypeJournal Article
Year of Publication2015
AuthorsNakada, T, Boyd, JH, Russell, JA, Aguirre-Hernandez, R, Wilkinson, MD, Thair, SA, Nakada, E, McConechy, MK, Fjell, CD, Walley, KR
JournalJournal of Innate Immunity
Volume7
Issue5
Pagination545-53
Date Published08/2015
ISSNPrint: 1662-811X; Online: 1662-8128
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.

DOI10.1159/000381265