COVID-19 severity varies widely across populations, partially driven by host genetics regulating SARS-CoV-2 entry. Transmembrane protease serine 2 (TMPRSS2) cleaves the viral spike protein to enable host cell invasion. In a new study, published in the Journal of Biosafety and Biosecurity, researchers from Jordan University of Science and Technology examined single-nucleotide polymorphisms (SNPs) in the TMPRSS2 gene (rs2070788 and rs12329760) for their association with COVID-19 susceptibility and severity in Jordanians.
The team found that rs2070788 and rs12329760 serve as promising genetic biomarkers to stratify Jordanian individuals at high risk of COVID-19 infection or critical progression, supporting targeted clinical risk management during viral outbreaks.
Single-nucleotide polymorphisms
In the study, participants were split into 434 COVID-19 cases and 427 uninfected controls. Cases were further stratified into 166 severe patients (hypoxemia requiring hospital/ventilation support) and 268 non-severe patients with mild-to-moderate symptoms.
Blood DNA was genotyped via PCR-RFLP, with demographic, anthropometric and comorbidity data collected for multivariate adjustment. All genotype distributions satisfied Hardy–Weinberg equilibrium.
The researchers found that rs2070788 (intronic G>A) correlated strongly with COVID-19 susceptibility across all genetic models (P<0.01). The GG genotype and G allele exerted protective effects: multivariate logistic regression confirmed carriers of GA or AA genotypes faced significantly higher infection odds (OR=0.599, 0.467 respectively).
In contrast, rs12329760 (coding C>T, altering enzyme catalytic function) showed no connection to infection susceptibility overall.
For disease severity, rs2070788 genotypes did not differ between severe and non-severe subgroups, while rs12329760 C/T heterozygotes had elevated severe disease risk under dominant and over-dominant models (P<0.05). Haplotype analysis reinforced these results: the AC haplotype raised COVID-19 infection risk, whereas GT haplotype carriers had markedly lower severe illness odds (P=0.011).
Age, sex and other covariates
Clinical covariates also shaped outcomes. Higher BMI and older age independently increased severe COVID-19 risk; males were overrepresented in severe and hospitalized groups, while females experienced milder disease.
Notably, diabetes and hypertension emerged as major comorbid risk factors for critical illness, though smoking correlated with lower infection risk—a finding likely distorted by confounding bias rather than true protection.
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Consistent with Turkish and Kurdish research, this study validates rs2070788 as a susceptibility marker and rs12329760 as a severity predictor, but conflicting results from European, Iranian and Latin American cohorts highlight population-specific genetic backgrounds as a key source of heterogeneity.
The researchers noted limitations such as restricted sampling from northern/central Jordan, exclusion of COVID-19 fatalities, and missing data on viral strains and vaccination status.
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