Could genetic variants in host cell receptors (ACE2) explain COVID-19 susceptibility among certain ethnic groups?

Anyone is vulnerable to becoming infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the virus that causes coronavirus disease 2019 (COVID-19). But some racial and ethnic groups are more at risk than others.

The COVID-19 pandemic has disproportionally affected certain groups for many reasons, including racial disparities in medical care, prior comorbidities, and working in occupations that increase exposure risk. According to a new study, angiotensin-converting enzyme 2 (ACE2) genetic variants may also help explain differences in infection rates among ethnic groups.

ACE2 is a receptor expressed on host cells that SARS-CoV-2 latches onto to instigate viral entry.

Led by Ioannis Karakikes of Stanford University, a new study suggests some hospitalized patients with COVID-19 contain ACE2 genetic variants that increase ACE2 expression. Some variants that altered ACE2 protein expression and binding affinity were more prevalent in people with European backgrounds.

By evaluating genetic data from patients with COVID-19, the researchers suggest it may be possible to predict who is susceptible to severe disease.

The team writes:

We provide evidence of a genetic link between the ACE2 genotype and COVID-19 disease severity and suggest that both eQTLs and coding variants may inform COVID-19 risk stratification.”

The study “SARS-CoV-2 susceptibility and ACE2 gene variations within diverse ethnic backgrounds” was published on the preprint medRxiv* server.

How they did it

The study aimed to investigate a potential biological cause that could explain the ethnic differences in susceptibility for SARS-CoV-2. More specifically, the researchers looked for any associations between ACE2 genetic variants affecting ACE2 protein structure and expression to testing positive for SARS-CoV-2.

The researchers evaluated whole-genome sequencing data of ACE2 variants from 6,274 patients who tested for COVID-19 infection. Of the 6,274 patients, about 1,837 tested positive for the virus. In patients who tested positive for the virus, 77% were not hospitalized. About 23% were hospitalized or died.

Whole-genome sequencing data evaluating ACE2 variants and expression quantitative trait loci (eQTL) distribution were also collected from a separate group of 37,207 individuals who served as controls. These individuals had no history of COVID-19.

Ethnic differences in hospitalized patients with COVID-19 illness

From the positive cases, about 68.3% were of European descent, 17.5% were South Asian, and 2.7% were of African descent. People of East Asian (0.8%) and Ad Mixed American (0.2%) backgrounds made up the lowest number of cases. Approximately 10.5% of people were labeled as Other.

The results confirmed that hospitalized patients with COVID-19 were statistically different across ethnic groups.

People of East Asian descent made up a low percentage of COVID-19 cases. However, they, as well as people of African background, were 50% more likely to be hospitalized compared to Europeans.

In contrast, people of South Asian descent were hospitalized for SARS-CoV-2 infection at a far lesser rate than East Asians (16.2% vs. 46.8%).

ACE2 genetic variants influence prognostic outcomes

Results showed there were ACE2 variants —p.K26R, p.H378R, p. Y515N — that affected the binding affinity between the coronavirus spike protein and ACE2.

The prevalence of these variants varied among ethnicities. The European population was more likely to have two missense variants p.K26R and p.N720D. The researchers suggest the K26R may be increasing SARS-CoV-2 spike protein binding affinity. They also hypothesize that having the N720D variant may be helping viral entry by increasing TMPRSS2 activation.

East Asians were less likely to have the Y497H variant. Consistent with prior research, the study found that East Asian populations are associated with variants of higher ACE2 expression. Having increased ACE2 expression may increase vulnerability to COVID-19 infection.

In contrast, people of African backgrounds displayed lower ACE2 expression levels, suggesting a potential protective effect with some ACE2 genetic variants.

Some variants could decrease ACE2 protein levels. People who had no history of prior SARS-CoV-2 infection were more likely to have the rs12006793 eQTL. Possessing this genetic variant may influence a person’s infection risk.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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