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.
RCT Entities:
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 shockpatients. 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. VPS13Drs6685273 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 VPS13Drs6685273 that was significant in the same direction in both GWAS. The VPS13Drs6685273 C allele was associated with increased IL-6 production. Patients with septic shock who had the VPS13Drs6685273 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 VPS13Drs6685273 C allele was associated with increased IL-6 production in vitro. The patients with the VPS13Drs6685273 CC genotype had increased 28-day mortality and increased organ failure. VPS13D appears to regulate IL-6 production.
Authors: Jan J Vonk; Wondwossen M Yeshaw; Francesco Pinto; Anita I E Faber; Liza L Lahaye; Bart Kanon; Marianne van der Zwaag; Antonio Velayos-Baeza; Raimundo Freire; Sven C van IJzendoorn; Nicola A Grzeschik; Ody C M Sibon Journal: PLoS One Date: 2017-01-20 Impact factor: 3.240
Authors: James L Shen; Tina M Fortier; Yan G Zhao; Ruoxi Wang; Margit Burmeister; Eric H Baehrecke Journal: Curr Biol Date: 2021-05-20 Impact factor: 10.900