BACKGROUNDThere is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 . Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19. METHODSWe conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels. RESULTSWe detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10 −8 ) in the meta-analysis of the two case-control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P = 1.15×10 −10 ; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P = 4.95×10 −8 , respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group-specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P = 1.48×10 −4 ) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P = 1.06×10 −5 ). CONCLUSIONSWe identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.

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.

Summary Background Chronic hepatitis delta is a severe liver disease with rapid progression to cirrhosis. The impact of hepatitis delta virus (HDV)‐RNA on disease progression and interferon treatment in a real‐world cohort has been barely explored. Aim To assess the development of clinical events in a cohort of chronic hepatitis delta patients according to the presence or absence of HDV‐RNA Methods Multicentre study at four academic hospitals in Spain included anti‐HDV‐positive patients with compensated liver disease with a follow‐up ≥12 months. Results Among 2888 HBsAg‐positive subjects, 151 (5.2%) tested positive for anti‐HDV, and 118 were included (58% men; median age, 49 years; 73% detectable HDV‐RNA and 30% cirrhosis, most often in subjects with HDV‐RNA). After a median follow‐up of 8 years, subjects with initially detectable HDV‐RNA were more prone to developing cirrhosis (31% vs 0%, P = .002) and/or liver decompensation (28% vs 3%, P = .019). Mortality rate was 0.44 per 1000 person‐months. The probability of a clinical event was 6%, 25%, and 80% according to initial baseline‐event‐anticipation score. HDV‐RNA became undetectable in 21 (24%) subjects either due to interferon or spontaneously (48% vs 52%, P = .29). Liver decompensation was reduced in interferon‐treated patients (13% vs 38%, P = .026). Conclusions Subjects with persistently positive HDV‐RNA had a worse prognosis in terms of clinical events. Baseline‐event‐anticipation score is useful in predicting the risk of developing liver decompensation and hepatocellular carcinoma. Interferon was beneficial in reducing liver decompensation, even in the absence of virological response.

JBR has served as an advisor to GlaxoSmithKline and Deerfield Capital. His institution has received investigator-initiated grant funding from Eli Lilly, GlaxoSmithKline and Biogen for projects unrelated to this paper. DP has served as an advisory board, and has received travel/research grants, speaking and teaching fees for Macopharma,

Background: Spontaneous HDV-RNA fluctuations, assessed by nonstandardised inhouse assays, have been reported during the course of chronic hepatitis delta (CHD).Aims: To evaluate changes in serum HDV-RNA concentrations in untreated CHD patients and correlate these changes with other HBV markers.Methods: A total of 323 consecutive serum samples from 56 CHD patients (detectable HDV-RNA) followed for >3 years were retested for HDV-RNA levels by a sensitive technique using the first WHO international HDV-RNA standard. Quantitative HBsAg, HBV-DNA, and HBV-RNA were also determined.Results: Most participants were male, middle-aged, white European, and HBeAgnegative (82%). Almost half had liver cirrhosis and 64% were receiving nucleos(t)ide analogues. At inclusion, median-HDV-RNA was 5.3 (4.2-6.5) log 10 IU/mL, HBsAg 4.0 (3.5-4.3) log 10 IU/mL, and HBV-DNA 1.6 (1.0-2.6) log 10 IU/mL; ALT values were normal in 13 (23%). During a mean follow-up of 5.6 (3-16) years, 14 (25%) showed ≥2log 10 HDV-RNA decline, including 11 (20%) who spontaneously achieved undetectable HDV-RNA. Four patients (7%) lost HBsAg, with undetectable HDV-RNA. The remaining 42 (75%) had persistently detectable HDV-RNA. During follow-up, patients with a ≥2log 10 HDV-RNA decline showed a greater HBsAg drop (−0.7 ± 1.1 vs −0.09 ± 0.9 log IU/mL; P = 0.039) than those with a <2 log 10 HDV-RNA decline. Overall, ALT and HBV-DNA levels decreased over time. There were no differences in clinical outcomes between groups.Conclusions: One-quarter of untreated CHD patients showed a ≥2log 10 decline in HDV-RNA and 20% reached HDV-RNA undetectability during a mean follow-up of | 463 PALOM et AL. How to cite this article: Palom A, Sopena S, Riveiro-Barciela M, et al. One-quarter of chronic hepatitis D patients reach HDV-RNA decline or undetectability during the natural course of the disease.

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p &lt; 5x10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10−22 and p = 8.1x10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10−8) and ARHGAP33 (p = 1.3x10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (&lt;60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

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.

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.