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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.

Original publication

DOI

10.1016/j.ebiom.2016.08.043

Type

Journal article

Journal

EBioMedicine

Publication Date

10/2016

Volume

12

Pages

239 - 246

Addresses

Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Research group Clinical Epidemiology, CSCC, Jena University Hospital, Jena, Germany. Electronic address: andre.scherag@med.uni-jena.de.

Keywords

Humans, Sepsis, Disease Progression, Genetic Predisposition to Disease, Prognosis, Mortality, Cohort Studies, Reproducibility of Results, Chromosome Mapping, Genomics, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Time Factors, Female, Male, Genetic Variation, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Exome