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

Abstract

Background: There 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. Method: The 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. Findings: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1.4, 95% confidence interval [CI] 1.2-1.6) and COVID-19 related mortality (HR 1.5, 95%CI 1.3-1.8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2.0, 95%CI 1.6-2.6), venous thromboembolism (OR 1.7, 95%CI 1.2-2.4), and hepatic injury (OR 1.6, 95%CI 1.2-2.0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2.6, 95%CI 1.8-3.9) compared to those > 60 years OR 1.5 (95%CI 1.3-1.9, interaction p-value=0.04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31.8% (95%CI 27.6-36.2) were risk variant carriers, compared to 13.9% (95%CI 12.6-15.2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0.82 vs 0.84, p=0.016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. Interpretation: The 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. Funding: Funding was obtained by each of the participating cohorts individually.

The major genetic risk factor for severe COVID-19 does not show any association among South Asian populations

“…However, none of them showed any association with the rs10490770 (p > 0.3) (Table 1 ). It is interesting to note that this SNP (rs10490770) has been found to be associated with disease severity in the global data 8 . However, the lack of association for rs10490770 with COVID-19 cases or CFR in India is striking and suggests instead a complex susceptibility response among Indian populations.…”

“…Subsequently, the COVID-19 Host Genetics Initiative has corroborated this result 7 . The worldwide meta-analysis of the COVID-19 Host Genetics Initiative has identified 13 genetic loci associated with higher susceptibility or higher severity 8 .…”

An immunogenetic view of COVID-19

“…This genomic region has a large effect on COVID-19 morbidity and mortality. The effects are similar to or larger than the ones of most established risk factors and are age-dependent, such that the risk is higher in younger individuals ( Nakanishi et al, 2021 ).…”

Implementing Personalized Medicine in COVID-19 in Andalusia: An Opportunity to Transform the Healthcare System

“…This region, which is thought to be present in around 30% of people in South Asia and 8% in Europe, has been shown to increase between 1.5-and 2-times approximately an infected person's odds of developing severe COVID-19 [4,7,10]. Carriers of rs10490770, an SNP strongly linked to this chromosome region have increased the odds of several COVID-19 complications, including severe respiratory failure (odds ratio [OR] 2•0, 95%CI 1•6-2•6), venous thromboembolism (OR 1•7, 95%CI 1•2-2•4), and hepatic injury (OR 1•6, 95%CI 1•2-2•0) and higher odds of death or severe respiratory failure, which are especially relevant in patients ≤60 years (OR 2.6, 95%CI 1.8-3.9) compared to those >60 years (OR 1.5 (95%CI 1.3-1.9, interaction p-value = 0•04) [11]. rs11385942, another SNP strongly associated with this genetic variation, has shown no association to biomarkers of systemic inflammation, including the C-reactive protein, ferritin, IL-6 and circulating neutrophils and lymphocytes but has been recently associated to increased amounts of the enhanced complement activation, both with C5a and terminal complement complex [12,13].…”