Genetic Variants within SARS-CoV-2 Human Receptor Genes May Contribute to Variable Disease Outcomes in Different Ethnicities

Adimulam, Theolan; Arumugam, Thilona; Gokul, Anmol; Ramsuran, Veron

doi:10.3390/ijms24108711

Cited by 10 publications

(9 citation statements)

References 178 publications

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“…In this sense, the variants p.Gly8Val/c.23G>T (rs75603675) and p.Val197Met/c.589G>A (rs12329760) have been reported to influence its interaction with ACE2 and the S protein ( 29 , 31 , 32 ). rs2070788 has been reported to be highly expressed in the lungs of patients at risk of developing severe COVID-19 ( 33 ), suggesting that these variants could play an important role in the severity of SARS-CoV-2 infection ( 34 – 36 ). Nevertheless, the study of TMPRSS2 polymorphisms has been described in some populations with contradictory results ( 37 – 39 ).…”

Section: Discussionmentioning

confidence: 99%

The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes

Martínez-Gómez,

Martinez-Armenta,

Tusie-Luna

et al. 2024

Front. Immunol.

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IntroductionSerine proteases play a critical role during SARS-CoV-2 infection. Therefore, polymorphisms of transmembrane protease serine 2 (TMPRSS2) and serpine family E member 1 (SERPINE1) could help to elucidate the contribution of variability to COVID-19 outcomes.MethodsTo evaluate the genetic variants of the genes previously associated with COVID-19 outcomes, we performed a cross-sectional study in which 1536 SARS-CoV-2-positive participants were enrolled. TMPRSS2 (rs2070788, rs75603675, rs12329760) and SERPINE1 (rs2227631, rs2227667, rs2070682, rs2227692) were genotyped using the Open Array Platform. The association of polymorphisms with disease outcomes was determined by logistic regression analysis adjusted for covariates (age, sex, hypertension, type 2 diabetes, and obesity).ResultsAccording to our codominant model, the GA genotype of rs2227667 (OR=0.55; 95% CI = 0.36-0.84; p=0.006) and the AG genotype of rs2227667 (OR=0.59; 95% CI = 0.38-0.91; p=0.02) of SERPINE1 played a protective role against disease. However, the rs2227692 T allele and TT genotype SERPINE1 (OR=1.45; 95% CI = 1.11-1.91; p=0.006; OR=2.08; 95% CI = 1.22-3.57; p=0.007; respectively) were associated with a decreased risk of death. Similarly, the rs75603675 AA genotype TMPRSS2 had an OR of 1.97 (95% CI = 1.07-3.6; p=0.03) for deceased patients. Finally, the rs2227692 T allele SERPINE1 was associated with increased D-dimer levels (OR=1.24; 95% CI = 1.03-1.48; p=0.02).DiscussionOur data suggest that the rs75603675 TMPRSS2 and rs2227692 SERPINE1 polymorphisms are associated with a poor outcome. Additionally, rs2227692 SERPINE1 could participate in hypercoagulable conditions in critical COVID-19 patients, and this genetic variant could contribute to the identification of new pharmacological targets and treatment strategies to block the inhibition of TMPRSS2 entry into SARS-CoV-2.

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Section: Discussionmentioning

confidence: 99%

The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes

Martínez-Gómez,

Martinez-Armenta,

Tusie-Luna

et al. 2024

Front. Immunol.

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“…The clinical manifestations of COVID-19, a viral infection due to SARS-CoV-2, vary from individual to individual and even between communities with different genetic backgrounds [1]. In particular, there is a wealth of evidence suggesting that COVID-19 was less severe in Africa compared to other continents, possibly due to demography, social economy, genetics, and a 'trained immunity' [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…Although it is evident that immune responses play a significant role in COVID-19 clinical outcomes, the mechanisms underlying this heterogeneity are still elusive [15]. It is possible that genetic diversity can explain these variations [1], but the mechanistic characterisation of immune responses will help identify early markers of disease severity in different settings and populations.…”

Section: Introductionmentioning

confidence: 99%

Cytokine Kinetics during Progression of COVID-19 in Rwanda Patients: Could IL-9/IFNγ Ratio Predict Disease Severity?

Ndoricyimpaye,

Van Snick,

Robert

et al. 2023

IJMS

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For effective treatments and preventive measures against severe COVID-19, it is essential to determine early markers of disease severity in different populations. We analysed the cytokine kinetics of 129 COVID-19 patients with mild symptoms, 68 severe cases, and 20 healthy controls for the first time in Rwanda. Pro-inflammatory (IFNγ, IL-6, TNFα), Treg (IL-10, TGFβ1, TGFβ3), Th9 (IL-9), Th17 (IL-17), and Th2 (IL-4, IL-13) cytokines, total IgM and IgG, as well as gene expressions of FoxP3, STAT5+, IFNγ-R1, and ROR alpha+, were measured at day 1, day 7, day 14, day 21, and day 28 post-infection. Severe cases showed a significantly stronger increase than mild patients in levels of all cytokines (except IL-9) and all gene expression on day 1 of infection. Some cytokine levels dropped to levels comparable to mild cases at later time points. Further analysis identified IFNγ as a marker of severity throughout the disease course, while TGFβ1, IL-6, and IL-17 were markers of severity only at an early phase. Importantly, this study revealed a striking low IL-9 level and high IFNγ/IL-9 ratio in the plasma of patients who later died compared to mild and severe cases who recovered, suggesting that this could be an important biomarker for predicting the severity of COVID-19 and post-COVID-19 syndrome.

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“…There is growing evidence that genetic factors also contribute to the severity of COVID-19 [ 8 , 9 ]. Disease severity has been categorized according to the symptoms experienced by COVID-19-positive individuals.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, these SNPs are found within predicted micro-RNA binding sites, with rs8259 ( CD147 ) being a predicted binding point for miR-492 and rs10080 ( NRP1 ) being a predicted binding point for miR-338 [ 30 , 37 , 38 , 39 ]. We recently reviewed 42 SNPs within ACE2 (12), TMPRSS2 (10), NRP1 (15) and CD147 (5) and found that rs2285666 (ACE2), rs12329769 (TMPRSS2), rs10080 (NRP1) and rs8259 (CD147) are significantly associated with COVID-19 co-morbidities within European and South Asian settings [ 9 ]. We selected these SNPs as a starting point to investigate their association with COVID-19 severity and susceptibility in an African setting.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms within the SARS-CoV-2 Human Receptor Genes Associate with Variable Disease Outcomes across Ethnicities

Adimulam,

Arumugam,

Naidoo

et al. 2023

Genes

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The contribution of human genes to the variability of disease outcomes has been shown to be important across infectious diseases. Studies have shown mutations within specific human genes are associated with variable COVID-19 outcomes. We focused on the SARS-CoV-2 receptors/co-receptors to identify the role of specific polymorphisms within ACE2, TMPRSS2, NRP1 and CD147. Polymorphisms within ACE2 (rs2285666), TMPRSS2 (rs12329760), CD147 (rs8259) and NRP1 (rs10080) have been shown to associate with COVID-19 severity. Using cryopreserved samples from COVID-19-positive African, European and South Asian individuals within South Africa, we determined genotype frequencies. The genetic variant rs2285666 was associated with COVID-19 severity with an ethnic bias. African individuals with a CC genotype demonstrate more severe COVID-19 outcomes (OR = 7.5; 95% CI 1.164–80.89; p = 0.024) compared with those with a TT genotype. The expressions of ACE2 and SARS-CoV-2 viral load were measured using droplet digital PCR. Our results demonstrate rs2285666 and rs10080 were significantly associated with increased SARS-CoV-2 viral load and worse outcomes in certain ethnicities. This study demonstrates two important findings. Firstly, SARS-CoV-2 viral load is significantly lower in Africans compared with individuals of European and South Asian descent (p = 0.0002 and p < 0.0001). Secondly, SARS-CoV-2 viral load associates with specific SARS-CoV-2 receptor variants. A limited number of studies have examined the receptor/co-receptor genes within Africa. This study investigated genetic variants within the SARS-CoV-2 receptor/co-receptor genes and their association with COVID-19 severity and SARS-CoV-2 viral load across different ethnicities. We provide a genetic basis for differences in COVID-19 severity across ethnic groups in South Africa, further highlighting the importance of further investigation to determine potential therapeutic targets and to guide vaccination strategies that may prioritize specific genotypes.

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Genetic Variants within SARS-CoV-2 Human Receptor Genes May Contribute to Variable Disease Outcomes in Different Ethnicities

Cited by 10 publications

References 178 publications

The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes

The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes

Cytokine Kinetics during Progression of COVID-19 in Rwanda Patients: Could IL-9/IFNγ Ratio Predict Disease Severity?

Polymorphisms within the SARS-CoV-2 Human Receptor Genes Associate with Variable Disease Outcomes across Ethnicities

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