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1.
Hum Mol Genet ; 2022 Jul 15.
Article in English | MEDLINE | ID: covidwho-1948292

ABSTRACT

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~ 0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.

2.
J Clin Invest ; 131(23)2021 12 01.
Article in English | MEDLINE | ID: covidwho-1546628

ABSTRACT

BackgroundThere is considerable variability in COVID-19 outcomes among younger adults, and some of this variation may be due to genetic predisposition.MethodsWe combined individual level data from 13,888 COVID-19 patients (n = 7185 hospitalized) from 17 cohorts in 9 countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications, and laboratory values. We next performed metaanalyses using FinnGen and the Columbia University COVID-19 Biobank.ResultsWe found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR, 1.4; 95% CI, 1.2-1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR, 2.1; 95% CI, 1.6-2.6), venous thromboembolism (OR, 1.7; 95% CI, 1.2-2.4), and hepatic injury (OR, 1.5; 95% CI, 1.2-2.0). Risk allele carriers age 60 years and younger had higher odds of death or severe respiratory failure (OR, 2.7; 95% CI, 1.8-3.9) compared with those of more than 60 years (OR, 1.5; 95% CI, 1.2-1.8; interaction, P = 0.038). Among individuals 60 years and younger who died or experienced severe respiratory failure, 32.3% were risk-variant carriers compared with 13.9% of those not experiencing these outcomes. This risk variant improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors.ConclusionsThe major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced among individuals 60 years or younger. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.


Subject(s)
Alleles , COVID-19 , Chromosomes, Human, Pair 3/genetics , Gene Frequency , Genetic Loci , Polymorphism, Genetic , SARS-CoV-2 , Age Factors , Aged , Aged, 80 and over , COVID-19/genetics , COVID-19/mortality , Female , Humans , Male , Middle Aged , Patient Acuity , Risk Factors
3.
J Pers Med ; 11(6)2021 May 26.
Article in English | MEDLINE | ID: covidwho-1244059

ABSTRACT

The COVID-19 pandemic represents an unprecedented opportunity to exploit the advantages of personalized medicine for the prevention, diagnosis, treatment, surveillance and management of a new challenge in public health. COVID-19 infection is highly variable, ranging from asymptomatic infections to severe, life-threatening manifestations. Personalized medicine can play a key role in elucidating individual susceptibility to the infection as well as inter-individual variability in clinical course, prognosis and response to treatment. Integrating personalized medicine into clinical practice can also transform health care by enabling the design of preventive and therapeutic strategies tailored to individual profiles, improving the detection of outbreaks or defining transmission patterns at an increasingly local level. SARS-CoV2 genome sequencing, together with the assessment of specific patient genetic variants, will support clinical decision-makers and ultimately better ways to fight this disease. Additionally, it would facilitate a better stratification and selection of patients for clinical trials, thus increasing the likelihood of obtaining positive results. Lastly, defining a national strategy to implement in clinical practice all available tools of personalized medicine in COVID-19 could be challenging but linked to a positive transformation of the health care system. In this review, we provide an update of the achievements, promises, and challenges of personalized medicine in the fight against COVID-19 from susceptibility to natural history and response to therapy, as well as from surveillance to control measures and vaccination. We also discuss strategies to facilitate the adoption of this new paradigm for medical and public health measures during and after the pandemic in health care systems.

4.
Rev Esp Enferm Dig ; 113(2): 125-135, 2021 02.
Article in English | MEDLINE | ID: covidwho-955196

ABSTRACT

BACKGROUND AND AIMS: SARS-CoV-2 is mainly a respiratory virus that has relevant systemic effects. We assessed the impact of baseline liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin) on COVID-19-related outcomes, including mortality, intensive care unit (ICU) admissions, and non-fatal severe complications. METHODS: after a systematic review of the relevant studies the odds ratio (OR), mean difference, sensitivity, specificity, and both positive and negative likelihood ratios were calculated for the prediction of relevant COVID-19 outcomes by performing a meta-analysis using fixed and random effects models. A Fagan nomogram was used to assess clinical usefulness. Heterogeneity was explored by sensitivity analysis and univariate meta-regression. RESULTS: twenty-six studies were included (22 studies and 5,271 patients for AST, 20 studies and 5,440 subjects for ALT, and nine studies and 3,542 patients for bilirubin). The outcomes assessed by these studies were: survival (n = 8), ICU admission (n = 4), and non-fatal severe complications (n = 16). AST > upper limit of normal (ULN) (OR: 3.10 [95 % CI, 2.61-3.68]), ALT > ULN (OR: 2.15 [95 % CI, 1.43-3.23]), and bilirubin > ULN (OR: 2.78 [95 % CI, 1.88-4.13]) were associated with an increased prevalence of severe complications with a specificity of 78 %, 77 %, and 94 %, respectively. The mean difference between mild and severe COVID-19 was 10.7 U/l (95 % CI, 5.8-15.6) for AST, 8 U/l (95 % CI, 1.0-15) for ALT, and 0.3 mg/dl (95 % CI, 0.16-0.45) for bilirubin. CONCLUSIONS: patients showing liver injury had a significantly higher risk of developing severe COVID-19 as compared to those with normal liver function tests at admission. We should include the assessment of AST, ALT, and total bilirubin (TB) routinely in the workup of patients affected by SARS-CoV-2 in order to predict those at risk of developing COVID-19-related outcomes.


Subject(s)
COVID-19/complications , COVID-19/physiopathology , Liver Diseases/etiology , Liver Diseases/physiopathology , Liver/physiopathology , Humans , Liver Function Tests , Severity of Illness Index
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