Identification of a Nonsynonymous Polymorphism in the SVEP1 Gene Associated With Altered Clinical Outcomes in Septic Shock*.

TitleIdentification of a Nonsynonymous Polymorphism in the SVEP1 Gene Associated With Altered Clinical Outcomes in Septic Shock*.
Publication TypeJournal Article
Year of Publication2015
AuthorsNakada, T-aki, Russell, JA, Boyd, JH, Thair, SA, Walley, KR
JournalCrit Care Med
Volume43
Issue1
Pagination101-8
Date Published2015 Jan
ISSN1530-0293
Abstract

OBJECTIVES: Mortality from septic shock is highly heritable. The identification of causal genetic factors is insufficient. To discover key contributors, we first identified nonsynonymous single-nucleotide polymorphisms in conserved genomic regions that are predicted to have significant effects on protein function. We then test the hypothesis that these nonsynonymous single-nucleotide polymorphisms across the genome alter clinical outcome of septic shock.DESIGN: Genetic-association study plus in vitro experiment using primary cells plus in silico analysis using genomic DNA and protein database.SETTING: Twenty-seven ICUs at academic teaching centers in Canada, Australia, and the United States.PATIENTS: Patients with septic shock of European ancestry (n = 520).INTERVENTIONS: Patients with septic shock were genotyped for 843 nonsynonymous single-nucleotide polymorphisms in conserved regions of the genome and are predicted to have damaging effects from the protein sequence.MEASUREMENTS AND MAIN RESULTS: The primary outcome variable was 28-day mortality. Secondary outcome variables were organ dysfunction. Productions of adhesion molecules including interleukin-8, growth-regulated oncogene-α, monocyte chemoattractant protein-1, and monocyte chemoattractant protein-3 were measured in human umbilical vein endothelial cells after SVEP1 gene silencing by RNA interference. Patients with septic shock having the SVEP1 C allele of nonsynonymous single-nucleotide polymorphism, SVEP1 c.2080A>C (p. Gln581His, rs10817033), had a significant increase in the hazard of death over the 28 days (hazard ratio, 1.72; 95% CI, 1.31-2.26; p = 9.7 × 10-5) and increased organ dysfunction and needed more organ support (p < 0.05). Silencing SVEP1 significantly increased interleukin-8, growth-regulated oncogene-α, monocyte chemoattractant protein-1, monocyte chemoattractant protein-3 production in human umbilical vein endothelial cells under lipopolysaccharide stimulation (p < 0.01).CONCLUSIONS: C allele of SVEP1 c.2080A>C (p. Gln581His) single-nucleotide polymorphism, a non-synonymous single-nucleotide polymorphism in conserved regions and predicted to have damaging effects on protein structure, was associated with increased 28-day mortality and organ dysfunction of septic shock. SVEP1 appears to regulate molecules of the leukocyte adhesion pathway.

DOI10.1097/CCM.0000000000000604
Alternate JournalCrit. Care Med.
PubMed ID25188548