Genetic factors of the disease course after sepsis: a genome-wide study for 28 day mortality
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 evidenc...
Main Authors: | , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Journal article |
Language: | English |
Published: |
Elsevier
2016
|
_version_ | 1797075761025253376 |
---|---|
author | Scherag, A Schöneweck, F Kesselmeier, M Taudien, S Platzer, M Felder, M Sponholz, C Rautanen, A Hill, A Hinds, C Hossain, H Suttorp, N Kurzai, O Slevogt, H Giamarellos-Bourboulis, E Armaganidis, A Trips, E Scholz, M Brunkhorst, F |
author_facet | Scherag, A Schöneweck, F Kesselmeier, M Taudien, S Platzer, M Felder, M Sponholz, C Rautanen, A Hill, A Hinds, C Hossain, H Suttorp, N Kurzai, O Slevogt, H Giamarellos-Bourboulis, E Armaganidis, A Trips, E Scholz, M Brunkhorst, F |
author_sort | Scherag, A |
collection | OXFORD |
description | 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. |
first_indexed | 2024-03-06T23:54:46Z |
format | Journal article |
id | oxford-uuid:73d54cc5-b034-40be-8173-59c1a30133a9 |
institution | University of Oxford |
language | English |
last_indexed | 2024-03-06T23:54:46Z |
publishDate | 2016 |
publisher | Elsevier |
record_format | dspace |
spelling | oxford-uuid:73d54cc5-b034-40be-8173-59c1a30133a92022-03-26T19:58:58ZGenetic factors of the disease course after sepsis: a genome-wide study for 28 day mortalityJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:73d54cc5-b034-40be-8173-59c1a30133a9EnglishSymplectic Elements at OxfordElsevier2016Scherag, ASchöneweck, FKesselmeier, MTaudien, SPlatzer, MFelder, MSponholz, CRautanen, AHill, AHinds, CHossain, HSuttorp, NKurzai, OSlevogt, HGiamarellos-Bourboulis, EArmaganidis, ATrips, EScholz, MBrunkhorst, FSepsis 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. |
spellingShingle | Scherag, A Schöneweck, F Kesselmeier, M Taudien, S Platzer, M Felder, M Sponholz, C Rautanen, A Hill, A Hinds, C Hossain, H Suttorp, N Kurzai, O Slevogt, H Giamarellos-Bourboulis, E Armaganidis, A Trips, E Scholz, M Brunkhorst, F Genetic factors of the disease course after sepsis: a genome-wide study for 28 day mortality |
title | Genetic factors of the disease course after sepsis: a genome-wide study for 28 day mortality |
title_full | Genetic factors of the disease course after sepsis: a genome-wide study for 28 day mortality |
title_fullStr | Genetic factors of the disease course after sepsis: a genome-wide study for 28 day mortality |
title_full_unstemmed | Genetic factors of the disease course after sepsis: a genome-wide study for 28 day mortality |
title_short | Genetic factors of the disease course after sepsis: a genome-wide study for 28 day mortality |
title_sort | genetic factors of the disease course after sepsis a genome wide study for 28 day mortality |
work_keys_str_mv | AT scheraga geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT schoneweckf geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT kesselmeierm geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT taudiens geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT platzerm geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT felderm geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT sponholzc geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT rautanena geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT hilla geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT hindsc geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT hossainh geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT suttorpn geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT kurzaio geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT slevogth geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT giamarellosbourboulise geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT armaganidisa geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT tripse geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT scholzm geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality AT brunkhorstf geneticfactorsofthediseasecourseaftersepsisagenomewidestudyfor28daymortality |