Genetic variants of PIEZO1 associate with COVID-19 fatality

Abstract

COVID-19, caused by the SARS-CoV-2 virus, carries significant risk of mortality and has spread globally with devastating societal consequences. Endothelial infection has been identified as a feature of the disease and so there is motivation to determine the relevance of endothelial membrane mechanisms affecting viral entry and response. Here, through a study of patient data in UK Biobank released on 16 April 2020, we suggest relevance of PIEZO1, a non-selective cation channel protein that both mediates endothelial responses to mechanical force and unusually indents the cell membrane. PIEZO1 notably has roles that may also be relevant in red blood cell function, pulmonary inflammation, bacterial infection and fibrotic auto-inflammation. We provide evidence that single nucleotide polymorphisms (SNPs) in the gene encoding PIEZO1 are more common in individuals who test positive for SARS-CoV-2 regardless of pre-existing hypertension, myocardial infarction, stroke, diabetes mellitus or arthritis. Some of these SNPs are more common in African and Caribbean populations, which are groups that were recently shown to have greater susceptibility to infection. One of the SNPs is a missense mutation that results in an amino acid change in an evolutionarily conserved and previously unexplored N-terminal region PIEZO1. The data support the notion of genetic factors influencing SARS-CoV-2 infection and suggest a specific role for PIEZO1.

Hypotheses and facts for genetic factors related to severe COVID-19

“…There is evidence that membrane proteins such as ACE2 and TMPRSS2 are important in SARS-CoV-2 entry[ 54 , 101 ]. It is indisputable that viral entry is affected by other membrane proteins and lipids[ 102 , 103 ].…”

“…A genome sequence analysis showed that these SNPs vary in prevalence with ethnicity and that the most significant SNP (rs7184427) varies between 65% to 90%. The analysis also suggests that rs7184427 affects a residue that is highly evolutionarily conserved and therefore has functional importance for COVID-19 severity and fatality[ 101 ].…”

Untitled

“…A possible explanation of the substantial variation in susceptibility to SARS-CoV-2 virus and the wide unpredictability in COVID-19 manifestation is the variability in the host genetic background. In fact, emerging genome-wide association [17,18] and candidate gene association [19] studies have revealed an association between a host genetic risk factor and the severity of COVID-19 illness.…”