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. 2025 Apr 14:16:1558189.
doi: 10.3389/fgene.2025.1558189. eCollection 2025.

Genetic variants in TMPRSS2 influence SARS-CoV-2 infection susceptibility within Mexican Mestizos

Rebeca I Montero #  1 , Cinthia L Dionicio #  1   2 , Gino Noris  1 , Maricela Piña-Pozas  3   4 , Carla Santana  1 , Rocío Gómez  5
Affiliations

Genetic variants in TMPRSS2 influence SARS-CoV-2 infection susceptibility within Mexican Mestizos

Rebeca I Montero et al. Front Genet. .

Abstract

Since host genetics is one of the primary factors contributing to COVID-19 susceptibility and its clinical progression, several studies have focused on analysing the implications of genetic polymorphisms associated with COVID-19. These studies particularly emphasise on common variants in genes that are involved in the viral mechanism of host entry and in the host's response to infection. In this study, we explored the participation of 24 single nucleotide polymorphisms located on the ACE, ADAM17, FURIN, IFITM3, TMPRSS2 and VDR genes in SARS-CoV-2 infection susceptibility. Three of these SNPs in TMPRSS2 (rs75603675, OR = 1.86, 95%CI = 1.29-2.66, p ≤ 0.001; rs4303795, OR = 1.98, 95%CI = 1.38-2.84, p ≤ 0.001 and rs8134378, OR = 2.59, 95%CI = 1.28-5.21, p ≤ 0.01) had a significant association with an increased risk of infection. When comparing haplotype frequency distributions, the haplotypes CAG (OR = 7.34, 95%CI = 5.51-9.77), AGA (OR = 2.46, 95%CI = 1.12-5.44), and AGG (OR = 1.59, 95%CI = 1.17-2.16) presented significant associations, suggesting that TMPRSS2 influences SARS-CoV-2 infection susceptibility within Mexican Mestizos. These risk alleles and their haplotypes were found more frequently in the case group than in the reference group, contributing to at least a twofold increase in the risk of SARS-CoV-2 infection, a finding that was reinforced by meta-analyses.

Keywords: COVID-19; SARS-CoV-2 infection; TMPRSS2; gene polymorphism; rs4303795; rs75603675; rs8134378.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Plot summarising the risk alleles and the odds ratios obtained from allele and genotype comparisons between the case and reference groups for the seven TMPRSS2 polymorphisms explored using several genotype models. Footnote: The dominant and recessive combinations conducted were: rs4562985Dominant = AA + AT versus TT, rs4562985Recessive = AA vs. AT + TT; rs20707885Dominant = AA + AG vs. GG, rs20707885Recessive = AA vs. AG + GG; rs61735794Dominant = TT + TC vs. CC, rs61735794Recessive = TT vs. TC + CC; rs12329760Dominant = TT + TC vs. CC, rs12329760Recessive = TT vs. TC + CC; rs75603675Dominant = AA + AC vs. CC, rs75603675Recessive = AA vs. AC + CC; rs4303795Dominant = GG + GA vs. AA, rs4503795Recessive = GG vs. GA + AA; rs8134378Dominant = AA + AG vs. GG, rs8134378Recessive = AA vs. AG + GG.
FIGURE 2
FIGURE 2
Linkage disequilibrium heatmap on the reference group based on the genetic distances among the several polymorphisms studied in TMPRSS2 gene. Note: The intensity of the colours means the closeness between the SNPs and, in turn, their linkage disequilibrium.
FIGURE 3
FIGURE 3
Bar plot with the statistical differences (A), median-joining network (B), and multidimensional scale plot of F ST values (C), of haplotypes found in the case and reference groups and their comparisons with two populations from the one thousand genome project. Note: MXL, Mexican in Los Angeles, California; EUR, European populations. The alleles of the SNPs conforming to the haplotype are shown in the following order: rs75603675, rs4303795, rs8134378.
FIGURE 4
FIGURE 4
Forest plot obtained from the fixed effect model showing the risk contribution under the dominant and recessive models (when possible) in the four TMPRSS2 polymorphisms with risk association: (A) rs61735794, (B) rs75603675, (C) rs4303795 and (D) rs8134378.
See this image and copyright information in PMC

References

    1. Alvarez-Topete E., Torres-Sanchez L. E., Hernandez-Tobias E. A., Veliz D., Hernandez-Perez J. G., Lopez-Gonzalez M. L., et al. (2024). Circum-Mediterranean influence in the Y-chromosome lineages associated with prostate cancer in Mexican men: a Converso heritage founder effect? PLoS One 19 (8), e0308092. 10.1371/journal.pone.0308092 - DOI - PMC - PubMed
    1. Balzanelli M. G., Distratis P., Lazzaro R., Pham V. H., Tran T. C., Dipalma G., et al. (2022). Analysis of gene single nucleotide polymorphisms in COVID-19 disease highlighting the susceptibility and the severity towards the infection. Diagn. (Basel) 12 (11), 2824. 10.3390/diagnostics12112824 - DOI - PMC - PubMed
    1. Barash A., Machluf Y., Ariel I., Dekel Y. (2020). The pursuit of COVID-19 biomarkers: putting the spotlight on ACE2 and TMPRSS2 regulatory sequences, Front. Med., 7: 582793. 10.3389/fmed.2020.582793 - DOI - PMC - PubMed
    1. Barbosa-Rodrigues F. B., da Silva R., Ferreira-Dos Santos E., de Brito M. T. F., Soares da Silva A. L., de Meira-Leite M., et al. (2023). Association of polymorphisms of IL-6 pathway genes (IL6, IL6R and IL6ST) with COVID-19 severity in an amazonian population. Viruses 15 (5), 1197. 10.3390/v15051197 - DOI - PMC - PubMed
    1. Belkhir K., Borsa P., Chikhi L., Raufaste N., Bonhomme F. (2004). “GENETIX 4.05, logiciel sous Windows TM pour la genetique des populations,” in Laboratoire genome, populations, interactions, CNRS UMR 5000 (France: Universite de Montpellier II; ).

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