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.
Highlights
2 Introduction 3 The COVID-19 pandemic has led to the death of millions of individuals and the largest 4 economic contraction since the Great Depression (1)
We explored the association of the rs10490770 risk allele with laboratory values, which are 5 known to be associated with the severity of COVID-19 (22–26). rs10490770 risk allele carrier 6 status was associated with the worst value for each of these laboratory values at hospital (e.g. 7 lactate dehydrogenase: 0.23 SD increase, p=3.5x10-7, D-dimer: 0.14 SD increase, p=2.1x10-3 and 8 interleukin-6: 0.16 SD increase, p=8.7x10-3; Supplemental Table 6, Supplemental Figure 2-3)
Combining individual-level clinical and genomic data from 13,888 individuals ascertained for 2 COVID-19 outcomes from 17 cohorts in nine countries, we found that the major genetic risk 3 factor for severe COVID-19 on chromosome 3 was strongly associated with COVID-19 related 4 mortality and clinical complications such as respiratory failure and venous thromboembolism
Summary
2 Introduction 3 The COVID-19 pandemic has led to the death of millions of individuals and the largest 4 economic contraction since the Great Depression (1). The clinical outcomes of COVID-19 are 5 remarkably variable, such that some individuals remain asymptomatic (2), while others develop 6 severe COVID-19 with systemic inflammation, respiratory failure or death. Amongst individuals ≤60 years who died or experienced severe respiratory failure, 32.3% were risk variant carriers, compared to 13.9% of those not experiencing these outcomes. This risk variant improved the prediction of death or severe respiratory failure to, or better than, most established clinical risk factors. The major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced amongst individuals ≤60 years. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management
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