Protective association of Klotho rs495392 gene polymorphism against hepatic steatosis in non-alcoholic fatty liver disease patients

Background/Aims@#Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic dysfunction. Among the multiple factors, genetic variation acts as important modifiers. Klotho, an enzyme encoded by the klotho (KL) gene in human, has been implicated in the pathogenesis of metabolic dysfunctions. However, the impact of variants in KL on NAFLD risk remains poorly understood. The aim of this study was to investigate the impact of KL rs495392 C>A polymorphism on the histological severity of NAFLD. @*Methods@#We evaluated the impact of the KL rs495392 polymorphism on liver histology in 531 Chinese with NAFLD and replicated that in the population-based Rotterdam Study cohort. The interactions between the rs495392, vitamin D, and patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 polymorphism were also analyzed. @*Results@#Carriage of the rs495392 A allele had a protective effect on steatosis severity (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.42–0.89; P=0.010) in Chinese patients. After adjustment for potential confounders, the A allele remained significant with a protective effect (OR, 0.66; 95% CI, 0.45–0.98; P=0.040). The effect on hepatic steatosis was confirmed in the Rotterdam Study cohort. Additional analysis showed the association between serum vitamin D levels and NAFLD specifically in rs495392 A allele carriers, but not in non-carriers. Moreover, we found that the rs495392 A allele attenuated the detrimental impact of PNPLA3 rs738409 G allele on the risk of severe hepatic steatosis. @*Conclusions@#The KL rs495392 polymorphism has a protective effect against hepatic steatosis in patients with NAFLD.

New susceptibility loci for severe COVID-19 by detailed GWAS analysis in European populations

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 3,260 COVID-19 patients with respiratory failure and 12,483 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 highly pleiotropic [~]0.9-Mb inversion polymorphism 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, 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.

A distinct metabolic profile associated with a fatal outcome in COVID-19 patients during early epidemic in Italy

Leveraging the unique biological resource based upon the initial COVID-19 patients in Policlinico di Milano (Italy), our study provides the first metabolic profile associated with a fatal outcome. The identification of potential predictive biomarkers offers a vital opportunity to employ metabolomics in a clinical setting as diagnostic tool of disease prognosis upon hospital admission.

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality

BackgroundThere is considerable variability in COVID-19 outcomes amongst younger adults--and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. MethodThe major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. FindingsWe found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1{middle dot}4, 95% confidence interval [CI] 1{middle dot}2-1{middle dot}6) and COVID-19 related mortality (HR 1{middle dot}5, 95%CI 1{middle dot}3-1{middle dot}8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2{middle dot}0, 95%CI 1{middle dot}6-2{middle dot}6), venous thromboembolism (OR 1{middle dot}7, 95%CI 1{middle dot}2-2{middle dot}4), and hepatic injury (OR 1{middle dot}6, 95%CI 1{middle dot}2-2{middle dot}0). Risk allele carriers [≤] 60 years had higher odds of death or severe respiratory failure (OR 2{middle dot}6, 95%CI 1{middle dot}8-3{middle dot}9) compared to those > 60 years OR 1{middle dot}5 (95%CI 1{middle dot}3-1{middle dot}9, interaction p-value=0{middle dot}04). Amongst individuals [≤] 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31{middle dot}8% (95%CI 27{middle dot}6-36{middle dot}2) were risk variant carriers, compared to 13{middle dot}9% (95%CI 12{middle dot}6-15{middle dot}2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those [≤] 60 years improved when including the risk allele (AUC 0{middle dot}82 vs 0{middle dot}84, p=0{middle dot}016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. InterpretationThe major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality--and these are more pronounced amongst individuals [≤] 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management. FundingFunding was obtained by each of the participating cohorts individually.

The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis

BackgroundRespiratory 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. MethodsWe 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. ResultsWe 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). ConclusionsWe 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.

SARS-CoV-2 seroprevalence trends in healthy blood donors during the COVID-19 Milan outbreak

ObjectivesThe Milan metropolitan area in Northern Italy was among the most severely hit by the SARS-CoV-2 outbreak. The epidemiological trends of mild COVID-19 are however still unknown. The aim of this study was to examine the seroprevalence of SARS-CoV-2 infection in healthy asymptomatic adults, the risk factors, and laboratory correlates. DesignWe conducted a cross-sectional study during the outbreak. Presence of anti-SARS-CoV-2 IgM/IgG antibodies against the Nucleocapsid protein was assessed by a lateral flow immunoassay. SettingBlood center at a leading academic hospital serving as COVID-19 referral center. ParticipantsWe considered a random sample of blood donors since the start of the outbreak (February 24th to April 8th 2020, n=789). Main outcome measuresThe main outcome was the prevalence of IgG/IgM anti-SARS-CoV-2 antibodies. ResultsThe test had a 98.3% specificity and 100% sensitivity, and for IgG+ was validated in a subset by an independent ELISA against the Spike protein (N=34, P<0.001). At the start of the outbreak, the overall seroprevalence of SARS-CoV-2 was 4.6% (2.3 to 7.9; P<0.0001 vs. 120 historical controls). During the study period characterized by a gradual implementation of social distancing measures, there was a progressive increase in seroprevalence to 7.1% (4.4 to 10.8), due to a rise in IgG+ to 5% (2.8 to 8.2; P=0.004 for trend, adjusted weekly increase 2.7{+/-}1.3%), but not of IgM+ (P=NS). At multivariate logistic regression analysis, seroconversion to IgG+ was more frequent in younger (P=0.043), while recent infections (IgM+) in older individuals (P=0.002). IgM+ was independently associated with higher triglycerides, eosinophils, and lymphocytes (P<0.05). ConclusionsSARS-CoV-2 infection was already circulating in Milan at the outbreak start. Social distancing may have been more effective in younger individuals, and by the end of April 4.4-10.8% of healthy adults had evidence of seroconversion. Asymptomatic infection may affect lipid profile and blood count. SUMMARY BOXO_ST_ABSWhat is already know on this topicC_ST_ABSO_LISARS-CoV-2 causes COVID-19, associated with a high mortality rate, but may be asymptomatic in a still undefined fraction of individuals. C_LIO_LICOVID-19 is associated with altered hematological, inflammatory and biochemical parameters, but the laboratory correlates of non-severe infection are unknown. C_LIO_LIA severe COVID-19 outbreak severely hit Milan at the end of February 2020, but the number of infected individuals and risk factors remain unclear. C_LI What this study addsO_LISARS-CoV-2 was already circulating in Milan at the COVID-19 outbreak start on February 2020, with only 1 in 20 infected individuals being symptomatic and diagnosed. C_LIO_LISocial distancing may have been more effective in reducing new infections in younger individuals, and by the end of April 4.4-10.8% of healthy asymptomatic adults had evidence of seroconversion. C_LIO_LIAsymptomatic infection may affect lipid profile and be associated with higher circulating lymphocytes and eosinophils. C_LI