Regional TMPRSS2 V197M Allele Frequencies Are Correlated with COVID-19 Case Fatality Rates

Jeon, Sungwon; Blažytė, Asta; Yoon, Changhan; Ryu, Hyojung; Jeon, Yeonsu; Bhak, Youngjune; Bolser, Dan; Manica, Andrea; Shin, Eun‐Seok; Cho, Yun Sung; Kim, Byung Chul; Ryoo, Nam Hee; Choi, Hansol; Bhak, Jong

doi:10.14348/molcells.2021.2249

Cited by 12 publications

(8 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has also been predicted that rs12329760 could affect the stability of TMPRSS2 protease and have a protective effect on patients 28 . The frequency of rs12329760 is higher in East Asia than in European countries, and the elevated frequency is associated with a lower fatality rate 29 . In Madrid, a sequencing analysis of 23 cases of familial multiple sclerosis has shown that TMPRSS2 synonymous variants rs61735792 and rs61735794 were significantly associated with infection, whereas ACE2 and furin were not significantly associated with SARS-COV-2 infection 30 .…”

Section: Introductionmentioning

confidence: 95%

Potential Genes Associated with COVID-19 and Comorbidity

Feng¹,

Song²,

Guo³

et al. 2022

Int. J. Med. Sci.

View full text Add to dashboard Cite

Hypertension, diabetes mellitus, and coronary artery disease are common comorbidities and dangerous factors for infection and serious COVID-19. Polymorphisms in genes associated with comorbidities may help observe susceptibility and disease severity variation. However, specific genetic factors and the extent to which they can explain variation in susceptibility of severity are unclear. Therefore, we evaluated candidate genes associated with COVID-19 and hypertension, diabetes mellitus, and coronary artery disease. In particular, we performed searches against OMIM, NCBI, and other databases, protein-protein interaction network construction, and GO and KEGG pathway enrichment analyses. Results showed that the associated overlapping genes were TLR4, NLRP3, MBL2, IL6, IL1RN, IL1B, CX3CR1, CCR5, AGT, ACE, and F2. GO and KEGG analyses yielded 302 GO terms (q < 0.05) and 29 signaling pathways (q < 0.05), respectively, mainly including coronavirus disease-COVID-19 and cytokine-cytokine receptor interaction. IL6 and AGT were central in the PPI, with 8 and 5 connections, respectively. In this study, we identified 11 genes associated with both COVID-19 and three comorbidities that may contribute to infection and disease severity. The key genes IL6 and AGT are involved in regulating immune response, cytokine activity, and viral infection. Therefore, RAAS inhibitors, AGT antisense nucleotides, cytokine inhibitors, vitamin D, fenofibrate, and vaccines regulating non-immune and immune factors could be potential strategies to prevent and cure COVID-19. The study provides a basis for further investigation of genes and pathways with predictive value for the risk of infection and prognosis and could help guide drug and vaccine development to improve treatment efficacy and the development of personalised treatments, especially for COVID-19 individuals with common comorbidities.

show abstract

Section: Introductionmentioning

confidence: 95%

Potential Genes Associated with COVID-19 and Comorbidity

Feng¹,

Song²,

Guo³

et al. 2022

Int. J. Med. Sci.

View full text Add to dashboard Cite

show abstract

“…We identified five residues (173, 260, 263, 360 and 412 – numbering from the human TMPRSS2 sequence) that were significantly detected under positive selection by at least two independent methods (Table 1, Figure 3B). Of note, position 197, which is polymorphic in human TMPRSS2 (rs12329760, V197M) and may be associated with COVID-19 severity ((Jeon et al, 2021) p-value around 10 -5 above the 10 -8 significance threshold commonly used in GWAS multiple testing), encoded for a conserved valine in all non-human primate sequences. Because the SARS-CoV-2 – TMPRSS2 interface is currently unknown, only in silico molecular docking studies have predicted the substrate binding region (Brooke and Prischi, 2020; Hoffmann et al, 2020; Rangel et al, 2020; SENAPATI et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

Distinct evolutionary trajectories of SARS-CoV-2 interacting proteins in bats and primates identify important host determinants of COVID-19

Cariou

Picard

Guéguen

et al. 2022

Preprint

View full text Add to dashboard Cite

The COVID-19 pandemic is caused by SARS-CoV-2, a novel coronavirus that spilled from the bat reservoir. Despite numerous clinical trials and vaccines, the burden remains immense, and the host determinants of SARS-CoV-2 susceptibility and COVID-19 severity remain largely unknown. Signatures of positive selection detected by comparative functional-genetic analyses in primate and bat genomes can uncover important and specific adaptations that occurred at virus-host interfaces. Here, we performed high-throughput evolutionary analyses of 334 SARS-CoV-2 interacting proteins to identify SARS-CoV adaptive loci and uncover functional differences between modern humans, primates and bats. Using DGINN (Detection of Genetic INNovation), we identified 38 bat and 81 primate proteins with marks of positive selection. Seventeen genes, including the ACE2 receptor, present adaptive marks in both mammalian orders, suggesting common virus-host interfaces and past epidemics of coronaviruses shaping their genomes. Yet, 84 genes presented distinct adaptations in bats and primates. Notably, residues involved in ubiquitination and phosphorylation of the inflammatory RIPK1 have rapidly evolved in bats but not primates, suggesting different inflammation regulation versus humans. Furthermore, we discovered residues with typical virus-host arms-race marks in primates, such as in the entry factor TMPRSS2 or the autophagy adaptor FYCO1, pointing to host-specific in vivo important interfaces that may be drug targets. Finally, we found that FYCO1 sites under adaptation in primates are those associated with severe COVID-19, supporting their importance in pathogenesis and replication. Overall, we identified functional adaptations involved in SARS-CoV-2 infection in bats and primates, critically enlightening modern genetic determinants of virus susceptibility and severity.

show abstract

“…In fact, a substantial association between the COVID-19 case fatality and a nonsynonymous mutation in the TMPRSS2 V197M allele has been demonstrated. In East Asian countries, this was linked to decreased case fatality rates [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms and mutations of ACE2 and TMPRSS2 genes are associated with COVID-19: a systematic review

Wang

Liu

et al. 2022

Eur J Med Res

View full text Add to dashboard Cite

Objective To determine the effect of polymorphisms and mutations in angiotensin-converting enzyme 2 (ACE2) and Type 2 transmembrane serine proteases (TMPRSS2) genes on susceptibility to corona virus disease 2019 (COVID-19) and patient prognosis. Introduction From December 2019 to the current time, an outbreak of epidemic of COVID-19, characterized by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has occurred around the world. It is now clear that SARS-CoV-2 binds to human ACE2 receptors, with expression of these receptors correlated with the rate of SARS-CoV-2 infection and mortality. Polymorphisms in individual patient factors, such as ACE2 and TMPRSS2 genes have been linked with an increase in negative outcomes, although evidence to affirm remains debatable. Methods Here, we performed a systematic review, based on guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, with the aim of assessing whether polymorphisms in ACE2 and TMPRSS2 genes affect the COVID-19 condition. We extensively searched PubMed, MEDLINE, Embase, the Cochrane Library, and Web of Science databases, for relevant articles and reports published in English between December 2019 and December 2021. Results A total of 495 full-text articles were downloaded, of which 185 were excluded after preliminary examination as they were duplicates. Finally, 310 articles were evaluated, by reading their titles and abstracts, and 208 of them eliminated based on our selection criteria. Finally, 33 articles met our inclusion criteria and were included in the final assessment. Genetic data from 33,923 patients with COVID-19 drawn from the general population and deriving from over 160 regions and 50 countries, as well as approximately 560,000 samples from global-public genetic databases, were included in our analysis. Ultimately, we identified 10 SNPs and 21 mutations in the ACE2 gene, along with 13 SNPs and 12 variants in the TMPRSS2 gene, which may be associated with COVID-19. Conclusions ACE2 and TMPRSS2 play vital roles in the onset, development, and prognosis of SARS-CoV-2 infection, and have both been strongly associated with vulnerability, intensity, and the clinical result of COVID-19. Overall, these genetic factors may have potential for future development of personalized drugs and vaccines against COVID-19. Trial registration: CRD42021239400 in PROSPERO 2021.

show abstract

Regional TMPRSS2 V197M Allele Frequencies Are Correlated with COVID-19 Case Fatality Rates

Cited by 12 publications

References 63 publications

Potential Genes Associated with COVID-19 and Comorbidity

Potential Genes Associated with COVID-19 and Comorbidity

Distinct evolutionary trajectories of SARS-CoV-2 interacting proteins in bats and primates identify important host determinants of COVID-19

Polymorphisms and mutations of ACE2 and TMPRSS2 genes are associated with COVID-19: a systematic review

Contact Info

Product

Resources

About