Genetic susceptibility for severe Covid-19 symptoms with respiratory failure

1. In Italian and Spanish populations, the chromosome locus 3p21.31 was identified with associated enrichment in coronavirus disease 2019 (Covid-19) patients with respiratory failure.

2. Patients with blood group A were associated with higher risk of Covid-19 susceptibility compared to non-A blood group patients.

Evidence Rating Level: 2 (Good)

Study Rundown: The manifestations of coronavirus disease 2019 (Covid-19) range from mild symptoms to severe respiratory failure related to interstitial pneumonia and acute respiratory distress syndrome. Mortality rates are due to the subgroup of patients with severe symptoms; however, the pathogenesis of severe Covid-19 is poorly understood. As such, this study conducted a genomewide association study (GWAS) to determine which host genetic factors contribute to severe symptoms with respiratory failure. The study results found an enrichment of the 3p21.31 gene cluster in patients with severe symptoms, There was also increased risk with type A blood type and a protective effect from type O blood type. The retrospective cohort study was limited by the removal of patient samples from different ethnic groups to maintain ethnic homogeneity in the study. Therefore, the study does not account for the variation in Covid-19 susceptibility based on ethnicity. Nonetheless, this study’s results are significant, and its findings highlight certain patient genetic factors associated with increased risk of developing severe Covid-19 symptoms.

Click to read the study in NEJM

Relevant Reading: Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

In-Depth [retrospective cohort]: This retrospective cohort study recruited 1980 patients from 3 hospitals in Italy and 4 hospitals in Spain with an additional 2381 control participants from both countries. Patients included in the study were hospitalized with respiratory failure and had a confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA polymerase-chain-reaction test. Respiratory failure was defined as the use of oxygen supplementation or mechanical ventilation. Patients whose samples resulted in population outliers due to different minority ethnic identification were excluded from the study. DNA extraction was performed on all samples, and genotyping occurred through the Global Screening Array (Illumina). Single-nucleotide polymorphism (SNP) imputation on genome build GRCh38 was conducted to maximize genetic coverage. For analysis, a total of 8,965,091 SNPs were included in the Italian cohort and 9,140,716 SNPs in the Spanish cohort. The study determined allelic distribution between no mechanical ventilation compared to mechanical ventilation of any type. Through the genomewide association analysis, two loci were found to be associated with Covid-19 induced respiratory failure: GA or G variation at locus 3p21.31 (odds ratio for the GA allele, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.15×10⁻¹⁰) and the A or C SNP at locus 9q34.2 (odds ratio for the A allele, 1.32; 95% CI, 1.20 to 1.47; P=4.95×10⁻⁸). The GA variation at locus 3p21.31 was associated with reduced expression of CXCR6 and LZTFL1 has been shown to be strongly expressed in human lung cells. Furthermore, the variation at the locus was higher among patients who received mechanical ventilation compared to oxygen supplementation only (odds ratio, 1.70; 95% CI, 1.27 to 2.26; P=3.30×10⁻⁴). The locus 9q34.2 coincided with the ABO blood group locus. The analysis determined a higher risk for severe Covid-19 symptoms was found in patients with blood group A compared to other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P=1.48×10⁻⁴). Additionally, patients with blood group O presented with a protective effect for severe symptoms compared to other blood group (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P=1.06×10⁻⁵). Finally, there was no significant allele association for HLA loci and severity of Covid-19 symptoms. Taken together, a GWAS analysis of patients from Italy and Spain determined risk of severe Covid-19 symptoms were associated with enrichment in the 3p21.31 loci and ABO blood group locus.

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