GWAS-significant loci and severe COVID-19: analysis of associations, link with thromboinflammation syndrome, gene-gene, and gene-environmental interactions.

Objective: The aim of this study was to replicate associations of GWAS-significant loci with severe COVID-19 in the population of Central Russia, to investigate associations of the SNPs with thromboinflammation parameters, to analyze gene-gene and gene-environmental interactions.

Materials And Methods: DNA samples from 798 unrelated Caucasian subjects from Central Russia (199 hospitalized COVID-19 patients and 599 controls with a mild or asymptomatic course of COVID-19) were genotyped using probe-based polymerase chain reaction for 10 GWAS-significant SNPs: rs143334143 , rs111837807 , rs17078346 , rs17713054 , rs7949972 , rs61882275 , rs12585036 , rs67579710 , rs12610495 , rs9636867 .

Results: SNP rs17713054 was associated with increased risk of severe COVID-19 in the entire group (risk allele A, OR = 1.78, 95% CI = 1.22-2.6, = 0.003), obese individuals (OR = 2.31, 95% CI = 1.52-3.5, = 0.0002, ( = 0.0004)), patients with low fruit and vegetable intake (OR = 1.72, 95% CI = 1.15-2.58, = 0.01, ( = 0.02)), low physical activity (OR = 1.93, 95% CI = 1.26-2.94, = 0.0035, ( = 0.007)), and nonsmokers (OR = 1.65, 95% CI = 1.11-2.46, = 0.02). This SNP correlated with increased BMI ( = 0.006) and worsened thrombodynamic parameters (maximum optical density of the formed clot, D ( = 0.02), delayed appearance of spontaneous clots, Tsp ( = 0.02), clot size 30 min after coagulation activation, CS ( = 0.036)). SNP rs17078346 was linked with increased BMI ( = 0.01) and severe COVID-19 in obese individuals (risk allele C, OR = 1.72, 95% CI = 1.15-2.58, = 0.01, ( = 0.02)). SNP rs12610495 was associated with increased BMI ( = 0.01), severe COVID-19 in obese patients (risk allele G, OR = 1.48, 95% CI = 1.09-2.01, = 0.01, ( = 0.02)), and worsened thrombodynamic parameters (time to the start of clot growth, Tlag ( = 0.01)). For rs7949972 , a protective effect against severe COVID-19 was observed in non-obese patients (effect allele T, OR = 0.67, 95% CI = 0.47-0.95, = 0.02, ( = 0.04)), improving thrombodynamic parameters (CS ( = 0.02), stationary spatial clot growth rates, Vst ( = 0.02)). Finally, rs12585036 exhibited a protective effect against severe COVID-19 in males (protective allele A, OR = 0.51, 95% CI = 0.32-0.83, = 0.004). SNPs rs67579710 , -, rs17713054 , rs7949972 rs9636867 -were involved in two or more of the most significant G×G interactions ( ≤ 0.01). The pairwise combination rs67579710 , - × rs17713054 was a priority in determining susceptibility to severe COVID-19 (it was included in four of the top five most significant SNP-SNP interaction models).

Conclusion: Overall, this study represents a comprehensive molecular-genetic and bioinformatics analysis of the involvement of GWAS-significant loci in the molecular mechanisms of severe COVID-19, gene-gene and gene-environmental interactions, and provides evidence of their relationship with thromboinflammation parameters in patients hospitalized in intensive care units.