Identification of a nonsynonymous polymorphism in the SVEP1 gene associated with altered clinical outcomes in septic shock.

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. Genetic-association study plus in vitro experiment using primary cells plus in silico analysis using genomic DNA and protein database. Twenty-seven ICUs at academic teaching centers in Canada, Australia, and the United States. Patients with septic shock of European ancestry (n = 520). 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. 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). 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.