Genetic Factors of the Disease Course after Sepsis: A Genome-Wide Study for 28Day Mortality

Abstract

Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction that varies by host genomic factors. We conducted a genome-wide association study (GWAS) in 740 adult septic patients and focused on 28day mortality as outcome. Variants with suggestive evidence for an association (p≤10-5) were validated in two additional GWA studies (n=3470) and gene coding regions related to the variants were assessed in an independent exome sequencing study (n=74). In the discovery GWAS, we identified 243 autosomal variants which clustered in 14 loci (p≤10-5). The best association signal (rs117983287; p=8.16×10-8) was observed for a missense variant located at chromosome 9q21.2 in the VPS13A gene. VPS13A was further supported by additional GWAS (p=0.03) and sequencing data (p=0.04). Furthermore, CRISPLD2 (p=5.99×10-6) and a region on chromosome 13q21.33 (p=3.34×10-7) were supported by both our data and external biological evidence. We found 14 loci with suggestive evidence for an association with 28day mortality and found supportive, converging evidence for three of them in independent data sets. Elucidating the underlying biological mechanisms of VPS13A, CRISPLD2, and the chromosome 13 locus should be a focus of future research activities. ; The project was supported by the Paul-Martini-Sepsis Research Group, funded by the Thuringian Ministry of Education, Science and Culture (ProExcellence; grant PE 108-2); the public funded Thuringian Foundation for Technology, Innovation and Research (STIFT) and the German Sepsis Society (GSS); the Jena Center of Sepsis Control and Care (CSCC), funded by the German Ministry of Education and Research (BMBF; 01 EO 1002, 01 EO 1502). The VISEP and MAXSEP trials from the SepNet Study Group had been supported by a BMBF grant (01 KI 0106) and by unrestricted grants from B. Braun, HemoCue, Novo Nordisk, Astra Zeneca GmbH, Wedel, Germany and Bayer HealthCare, Leverkusen, Germany. The exome sequencing study was funded in part by the Hellenic Institute for the Study of Sepsis. The GenOSept study was supported by the European Union and benefits from the 6th framework programme of RTD funding. The PROGRESS study is supported by the German Federal Ministry of Education and Research, grant numbers 01KI07110 (Giessen), 01KI07111 (Jena), 01KI07113 (Leipzig), 01KI07114 (Berlin), 01KI1010I (Leipzig), and 01KI1010D (Greifswald).