Genome-wide association study of susceptibility to acute respiratory distress syndrome.

IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
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.

急性呼吸窘迫综合征易感性的全基因组关联研究。
背景:急性呼吸窘迫综合征(ARDS)是一种严重的肺部炎症过程,通常由败血症引起,在重症监护病房造成严重的死亡率负担。在这里,我们进行了ARDS的全基因组关联研究(GWAS),以确定遗传风险位点,从而帮助指导新的治疗方案的开发。方法:我们对来自三个独立研究的716例ARDS患者(主要与严重感染相关)和4399例风险对照进行了病例对照GWAS。对三项研究的结果进行荟萃分析,显著性设置为p < 5 × 10-8。在所有三项研究中,具有一致影响方向、可能重复和名义显著性(p < 0.05)的变异被宣布为暗示性关联。使用全外显子组测序数据对优先位点进行贝叶斯精细定位、计算机功能评估和基于基因的罕见变异崩溃分析。两项独立研究共纳入430例ARDS病例和1398例风险对照者作为验证样本。研究结果:我们在HMGCR附近发现了一个变异,该变异在全基因组范围内与ARDS显著相关,并且先前与胆固醇代谢有关。该位点与ANKDD1B在动脉中的表达相关。罕见的外显子变异分析显示,HMGCR与ARDS在名义水平上存在相关性(p < 0.05)。虽然在另外两个验证队列中没有达到名义上的显著性,但这一变异在所有5项研究中表现出一致的影响方向。解释:HMGCR附近的一种常见变异与ARDS风险相关,提示胆固醇代谢与ARDS风险之间存在联系。需要在独立研究中进行验证。资助:威康信托基金会、国家卫生研究所莱斯特生物医学研究中心、国家心脏、肺和血液研究所、ATS研究计划、加纳利亚政府、Fundación加纳利亚研究所Investigación加纳利亚卫生研究所Tecnológico y de Energías可再生研究所、特内里费岛卡比尔多研究所、卡洛斯三世研究所、国家机构Investigación、德国教育和研究部、图林根教育、科学和文化部、图林根技术、创新和研究基金会,德国败血症学会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
EBioMedicine
EBioMedicine Biochemistry, 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.
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