Genetic variations in the human severe acute respiratory syndrome coronavirus receptorACE2and serine proteaseTMPRSS2

Abstract

AimsThe recent emergence of novel, pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health emergency. The coronaviral entry requires the spike (S)-protein for attachment to the host cell surface, and employs human angiotensin-converting enzyme 2 (hACE2) for entry and transmembrane protease serine 2 (TMPRSS2) for S-protein priming. Although coronaviruses undergo evolution by mutating themselves, it is also essential to know the host genetic factors. Here, we describe the single nucleotide variations (SNVs) in human ACE2 and TMPRSS2.MethodsThe genetic variants derived from five population-sequencing projects were classified by variant type, allele frequency (AF), ethnic group and estimated pathogenicity. The SNVs in SARS-CoV-2/hACE2 contact residues were investigated. The genetic variability was normalised using non-linear regression and the total number of SNVs was estimated by the derived formulas.ResultsWe detected 349 and 551 SNVs in ACE2 and TMPRSS2, respectively, in a total of 156 513 individuals. The vast majority (>97%) of the SNVs were very rare (AF <0.1%) and population-specific, and were computationally estimated to be more frequently deleterious than the SNVs with high AF. These SNVs were distributed throughout the coding regions; some ACE2 variants were located in the SARS-CoV-2/hACE2 contact residues, with a hemizygous state occurring in males. Using regression analysis, the total numbers of genetic variations in ACE2 and TMPRSS2 were 1.1×103 and 1.5×103, respectively, for a population of one million people.ConclusionThe majority of SNVs in ACE2 and TMPRSS2 are rare, population-specific and deleterious, and a multitude of very rare SNVs may explain different susceptibility to SARS-CoV-2.

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.…”

Angiotensin-converting enzyme 2 and COVID-19: patients, comorbidities, and therapies

“…We may question whether genetic variations in ACE2 and TMPRSS2 among racial and ethnic groups exist. Fujikura and Vesaka ( 323 ) detected 349 and 551 single nucleotide variations in human ACE2 and TMPRSS2, respectively, in 156,513 individuals. The single nucleotide variations were rare but population specific and deleterious, suggesting susceptibility of different populations to SARS-CoV-2.…”

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

“…A maioria desses genes está relacionada ao sistema imunológico e aos órgãos respiratórios, o que enfatiza o fato de que a doença pulmonar obstrutiva crônica enfraquece esse sistema e torna os pacientes mais suscetíveis a desenvolver COVID-19 grave (Sharma, Pandey & Bhattacharyya, 2020). Além disso, a maioria das variações de nucleotídeo único em ACE2 e TMPRSS2 são raros, específicos para a população e deletérios, podendo explicar a suscetibilidade diferente ao SARS-CoV-2 (Fujikura et al, 2020).…”