The Pursuit of COVID-19 Biomarkers: Putting the Spotlight on ACE2 and TMPRSS2 Regulatory Sequences

Abstract

Diverse populations worldwide are differentially affected by coronavirus disease 2019 . While socioeconomic background has been studied extensively, little is known about the genetic variation underlying this phenomenon. This study is aimed at examining the genetic basis behind the great discrepancies among diverse ethnic groups in terms of COVID-19 susceptibility for viral infection, disease prognosis, and mortality. To this end, in silico analysis of single-nucleotide polymorphisms (SNPs) within regulatory sequences of the human angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2)-the virus's gateway to host cells-and their plausible implications on expression levels was conducted. We provide indication that the variation in the human ACE2 and TMPRSS2 regulatory sequences is likely to be involved in and contribute to this phenomenon. SNPs that are abundant in the more susceptible populations introduce binding sites (BSs) for transcription factors or they may invalidate BSs for transcription repressor-both may enhance target gene (ACE2 or TMPRSS2) expression in the relevant target tissues. SNPs that are abundant in the more resistant populations may invalidate BSs for a transcriptional repressor or they may introduce BSs for a transcriptional repressor or initiator of mRNA degradation, which may reduce target gene expression levels. This aspect, when added to the socioeconomic factors, can be a cause for the divergent prevalence of the disease and the different mortality rates within diverse populations. This demonstration may call for a shift in the paradigm of searching for COVID-19 biomarkers, such that SNPs within regulatory sequences should be of high importance.

Transmembrane serine protease 2 Polymorphisms and Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection: A German Case-Control Study

“…So far, mainly in silico studies have been performed to analyze the influence of variants in the gene TMPRSS2 with regard to COVID-19 ( Asselta et al, 2020 ; Barash et al, 2020 ; Fujikura and Uesaka, 2020 ; Ghafouri-Fard et al, 2020 ; Hou et al, 2020 ; Paniri et al, 2020 ; Russo et al, 2020 ; Senapati et al, 2020 ; Singh et al, 2020 ; Smatti et al, 2020 ; Vargas-Alarcón et al, 2020 ; Zarubin et al, 2020 ).…”

“…Single nucleotide polymorphisms (SNPs) in the gene TMPRSS2 (chromosome 21q22.3, reverse strand) have been associated with susceptibility to and severity of H1N1 or H1N9 influenza A virus infections ( Cheng et al, 2015 ). Currently, SNPs altering gene expression or protein function are frequently discussed in the light of Coronavirus disease 2019 (COVID-19) in literature reviews and in in silico analyses utilizing genotyping data from existing databases ( Asselta et al, 2020 ; Barash et al, 2020 ; Fujikura and Uesaka, 2020 ; Ghafouri-Fard et al, 2020 ; Hou et al, 2020 ; Paniri et al, 2020 ; Russo et al, 2020 ; Senapati et al, 2020 ; Singh et al, 2020 ; Smatti et al, 2020 ; Vargas-Alarcón et al, 2020 ; Zarubin et al, 2020 ). Three variants, rs2070788, rs383510, and rs12329760, seem to be of particular interest based on preliminary work in the context of other virus infections.…”

The Role of Immunogenetics in COVID-19

“…In the case of COVID-19, some authors proposed that polymorphism in ACE2 gene (located on chromosome X) coding and regulatory regions may partially explain such a sex-connected variability [ 11 ]. However, other factors may be involved, possibly including biochemical patterns ruling natural defenses against viruses (for example the sex related differences in H 2 S synthesis) as well as genes involved on immune responses located on chromosome X like CD40 ligand ( CD40L ), TLR7 , TLR8 , forkhead box p3 ( FOXP3 ) and C-X-C Motif Chemokine Receptor 3 ( CXCR3 ) [ 219 , 220 , 221 , 222 , 223 , 224 , 225 ].…”

“…Defining these factors will be especially advantageous to detect patients who may benefit from an early hospitalization and therapeutic intervention [ 2 , 3 ]. The attention was immediately captivated by those host genetic variants ruling the expression and characteristics of viral receptors and host enzymes involved in viral entry [ 1 , 3 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. However, this represents only one of the elements that must be considered in the complex interplay involving the virus, the host respiratory tract–lung tissues, and the host immune system [ 2 , 7 , 14 ].…”

Influência da suscetibilidade genética na incidência e mortalidade de COVID-19 (SARS-CoV-2)

“…Devido a isso, tem sido desenvolvido estudos direcionados para a criação de um tratamento que visa a inativação e/ou diminuição desse regulador em indivíduos do sexo masculino que foram infectados por essa patologia (Pereira et al, 2020). Estudos utilizando o gene ACE2 também apresentaram resultados semelhantes para esse mecanismo de ativação, visto que ambos os genes contribuem de maneira significativa para o aumento da entrada viral nos indivíduos (Barash et al, 2020;Choudhary et al, 2020;Latini, et al, 2020).…”