Beatriz Guillen-Guio, Eva Suarez-Pajes, Eva Tosco-Herrera, Tamara Hernandez-Beeftink, Jose Miguel Lorenzo-Salazar, Diana Chang, Rafaela González-Montelongo, Luis A Rubio-Rodríguez, Olivia C Leavy, Richard J Allen, Almudena Corrales, Raquel Cruz, Miguel Bardají-Carrillo, Angel Carracedo, Eduardo Tamayo, V Eric Kerchberger, Lorraine B Ware, Brian L Yaspan, Markus Scholz, André Scherag, Jesús Villar, Louise V Wain, Carlos Flores
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引用次数: 0
Abstract
Background: Acute respiratory distress syndrome (ARDS) is a severe inflammatory process of the lung, often due to sepsis, and poses significant mortality burden in intensive care units. Here we conducted a genome-wide association study (GWAS) of ARDS to identify genetic risk loci that can help guide the development of new therapeutic options.
Methods: We performed a case-control GWAS in 716 cases with ARDS, mainly associated with severe infections, and 4399 at-risk controls from three independent studies. Results were meta-analysed across the three studies, with significance set at p < 5 × 10-8. Suggestive associations were declared for variants exhibiting consistent direction of effects, likely to replicate and nominal significance (p < 0.05) in all three studies. Prioritised loci were subjected to Bayesian fine mapping, in-silico functional assessments, and gene-based rare variant collapsing analysis using whole-exome sequencing data. Two independent studies with 430 ARDS cases and 1398 at-risk controls served as validation samples.
Findings: We identified a variant near HMGCR that showed genome-wide significant association with ARDS and had been previously linked to cholesterol metabolism. This locus was associated with ANKDD1B expression in artery. The rare exonic variant analysis showed associations between HMGCR and ARDS at nominal level (p < 0.05). While no nominal significance was achieved in the two additional validation cohorts, this variant exhibited a consistent direction of effects across all 5 studies.
Interpretation: A common variant near HMGCR was associated with ARDS risk, suggesting a link between cholesterol metabolism and ARDS risk. Validation in independent studies is needed.
Funding: Wellcome Trust, National Institute for Health Research Leicester Biomedical Research Centre, National Heart, Lung, and Blood Institute, ATS Research Program, Gobierno de Canarias, Fundación Canaria Instituto de Investigación Sanitaria de Canarias, Instituto Tecnológico y de Energías Renovables, Cabildo Insular de Tenerife, Instituto de Salud Carlos III, Agencia Estatal de Investigación, German Ministry of Education and Research, Thuringian Ministry of Education, Science and Culture, the Thuringian Foundation for Technology, Innovation, and Research, German Sepsis Society.
EBioMedicineBiochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍:
eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.