GWAS-significant loci and severe COVID-19: analysis of associations, link with thromboinflammation syndrome, gene-gene, and gene-environmental interactions
Authors: Loktionov Alexey Valerevich , Kobzeva Ksenia Andreevna , Karpenko Andrey Romanovich , Sergeeva Vera Alexeevna , Orlov Yuriy Lvovich , Bushueva Olga Yurievna 
Published: August 2024

ObjectiveThe 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 MethodsDNA 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 CCHCR1, rs111837807 CCHCR1, rs17078346 SLC6A20-LLZTFL1, rs17713054 SLC6A20-LLZTFL1, rs7949972 ELF5, rs61882275 ELF5, rs12585036 ATP11A, rs67579710 THBS3, THBS3-AS1, rs12610495 DPP9, rs9636867 IFNAR2.ResultsSNP rs17713054 SLC6A20-LZTFL1 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, p = 0.003), obese individuals (OR = 2.31, 95% CI = 1.52–3.5, p = 0.0002, (pbonf = 0.0004)), patients with low fruit and vegetable intake (OR = 1.72, 95% CI = 1.15–2.58, p = 0.01, (pbonf = 0.02)), low physical activity (OR = 1.93, 95% CI = 1.26–2.94, p = 0.0035, (pbonf = 0.007)), and nonsmokers (OR = 1.65, 95% CI = 1.11–2.46, p = 0.02). This SNP correlated with increased BMI (p = 0.006) and worsened thrombodynamic parameters (maximum optical density of the formed clot, D (p = 0.02), delayed appearance of spontaneous clots, Tsp (p = 0.02), clot size 30 min after coagulation activation, CS (p = 0.036)). SNP rs17078346 SLC6A20-LZTFL1 was linked with increased BMI (p = 0.01) and severe COVID-19 in obese individuals (risk allele C, OR = 1.72, 95% CI = 1.15–2.58, p = 0.01, (pbonf = 0.02)). SNP rs12610495 DPP9 was associated with increased BMI (p = 0.01), severe COVID-19 in obese patients (risk allele G, OR = 1.48, 95% CI = 1.09–2.01, p = 0.01, (pbonf = 0.02)), and worsened thrombodynamic parameters (time to the start of clot growth, Tlag (p = 0.01)). For rs7949972 ELF5, 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, p = 0.02, (pbonf = 0.04)), improving thrombodynamic parameters (CS (p = 0.02), stationary spatial clot growth rates, Vst (p = 0.02)). Finally, rs12585036 ATP11A exhibited a protective effect against severe COVID-19 in males (protective allele A, OR = 0.51, 95% CI = 0.32–0.83, p = 0.004). SNPs rs67579710 THBS3, THBS3-AS1, rs17713054 SLC6A20-LZTFL1, rs7949972 ELF5, rs9636867 IFNAR2—were involved in two or more of the most significant G×G interactions (pperm ≤ 0.01). The pairwise combination rs67579710 THBS3, THBS3-AS1 × rs17713054 SLC6A20-LZTFL1 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).ConclusionOverall, 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.