ABSTRACT
Due to the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), deepening the host genetic contribution to severe COVID-19 may further improve our understanding about underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany, as well as hypothesis-driven targeted analysis of the human leukocyte antigen (HLA) region and chromosome Y haplotypes. We include detailed stratified analyses based on age, sex and disease severity. In addition to already established risk loci, our data identify and replicate two genome-wide significant loci at 17q21.31 and 19q13.33 associated with severe COVID-19 with respiratory failure. These associations implicate a highly pleiotropic ~0.9-Mb 17q21.31 inversion polymorphism, which affects lung function and immune and blood cell counts, and the NAPSA gene, involved in lung surfactant protein production, in COVID-19 pathogenesis.
Subject(s)
COVID-19 , Respiratory InsufficiencyABSTRACT
Background: The long-term effects of COVID-19 still remain to be explored. The purpose of this study is to describe the clinical complications of SARS-CoV-2 infection at one year after acute disease, either in inpatients and outpatients, and to explore associated risk factors, in particular disease severity during the acute phase.Methods: This study is part of a large cohort study of COVID+ patients. Seven-hundred seventeen patients from the metropolitan area of Milan in Lombardia (Italy) who had been referred for tele-monitoring after a confirmed or plausible SARS-CoV-2 infection between February and May 2020 were evaluated with a semi-structured phone interview between February and March 2021, regardless of the severity of the disease during the acute phase. In the phone interview performed by trained medical staff we looked for clinical complications in the following domains: respiratory disorders, fatigue and weakness, muscle and joint pain, movement impairments, neurological and cognitive impairments, sensory alterations, sleep disorders, and gastrointestinal symptoms. Patients were asked if symptoms were present before the SARS-CoV-2 infection, and if the symptom was present at the current time.Interpretation: At 12-months after acute infection, COVID-19 survivors were still suffering of symptoms identified at shorter follow-up including fatigue, pain and sleep disorders among the most frequent. A more severe impairment in the acute phase did not seem to predict more severe complications, further supporting the unpredictability of such consequences. These data need to be considered and compared with other studies from other countries on COVID-19 survivors and have to be taken into account to plan public health interventions.Funding: Fondazione Invernizzi and Regional Operational Programme (ERDF ROP) 2014-2020Declaration of Interest: None to declare. Ethical Approval: This study was approved by the Ethics Commission of the University of Milan, (Ethics Commission number: 126/20). Written informed consent was obtained from allparticipants.
Subject(s)
COVID-19 , Respiratory Tract Infections , Gastrointestinal Diseases , Muscle WeaknessABSTRACT
Background. Respiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients. Methods. We included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers, 835 patients and 1,255 population-derived controls from Italy, and 775 patients and 950 controls from Spain were included in the final analysis. In total we analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and conducted a meta-analysis of both case-control panels. Results. We detected cross-replicating associations with rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were genome-wide significant (P<5x10-8) in the meta-analysis of both study panels, odds ratio [OR], 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.14x10-10 and OR 1.32 (95% CI, 1.20 to 1.47; P=4.95x10-8), respectively. Among six genes at 3p21.31, SLC6A20 encodes a known interaction partner with angiotensin converting enzyme 2 (ACE2). The association signal at 9q34 was located at the ABO blood group locus and a blood-group-specific analysis showed higher risk for A-positive individuals (OR=1.45, 95% CI, 1.20 to 1.75, P=1.48x10-4) and a protective effect for blood group O (OR=0.65, 95% CI, 0.53 to 0.79, P=1.06x10-5). Conclusions. We herein report the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid-19 pathophysiology.