AUTHOR=Loktionov Alexey Valerevich , Kobzeva Ksenia Andreevna , Karpenko Andrey Romanovich , Sergeeva Vera Alexeevna , Orlov Yuriy Lvovich , Bushueva Olga Yurievna 

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

JOURNAL=Frontiers in Genetics

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1434681

DOI=10.3389/fgene.2024.1434681

ISSN=1664-8021

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