RESUMEN
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.
RESUMEN
Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization (MR) analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2: P=1.6x10-6, IFNAR2: P=9.8x10-11, and IL-10RB: P=1.9x10-14) using cis-eQTL genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared eQTL signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.
