More on the ACE2-Related Asian COVID-19 Susceptibility Hypothesis

James Lyons-Weiler, PhD – 2/16/2020

SCIENCE IS FOR ASKING QUESTIONS. When people started posting online the idea that “Asians”, especially male “Asians”, and perhaps people with the “Han genome” are generally more susceptible to morbidity (serious illness) and mortality (death) from SARS 2 infection leading to COVID-2019, the natural question then becomes “where is this coming from” and “what data are there to support this”? The alleged implications are that the risk of serious illness and death from SARS 2 infection might imply a that the SARS 2 virus is a bioweapon, made by the US, that targets “Asians” or people with the “Han genome”.

When scientists want to understand who is at risk, sometimes they look at genetic risk. While the ACE2 is gene is related to that for ACE, and variation in both genes sometimes co-contribute to risk of certain health outcomes (e.g., thyroid cancer, hypertension, kidney disease), ACE and ACE2 encode distinctly different proteins. So my earlier post that variation shared among ethnic groups in ACE would tend to rule out the logic of a genetically targeted bioweapon, the genetic variation I described was for ACE, not ACE2. The general lesson, however, still applies: any high-frequency genetic variation (inherited variation) in ACE2 would be shared across many ethnic groups, so it, too, would make a terrible bioweapon.

The confusion stems from a simple human error made in a Reddit forum where those poster shared a link to a study from 2007 on geographical variation in the “ACE II” genotype. As I explained in my article, ACE II is not ACE2 but instead refers to the ACE I/I genotype, where individual receive one allele at the ACE locus (not the ACE 2 locus) from mom, and one from dad. The other known allele is the D allele, and so there are three possible genotypes – I/I, I/D and D/D – that a person can have. Since the original Reddit post confused ACE2 and “ACE II”, I hope the post, which provides a basic lesson on inheritance patterns of genetic variation, clarifies.

But Still, Why the Focus on ACE2?

ACE2 is known to be a point of cellular entry for B-coronaviruses, notably SARS. There is this study (“The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells”) that shows, using data from a handful of people from China, that one of the males had a much larger amount of ACE2 gene expression in his lung tissue. Gene expression is a function of genetic variation, environment, and developmental programming in any tissue. In the studies I have been involved in that focus on gene expression studies (using either RNASeq or whole genome gene expression arrays), studies this small are called “pilot projects” and whole-population generalizations away much larger studies with data from many, many more patients. Even then such generalizations are only warranted if the studies can be replicated.

But let’s say that (hypothetically) that ACE2 is more highly expressed in Asian males (again, hypothetically) and reason out whether it makes sense as a marker for a targeted bioweapon. Some facts about ACE2 might aid in quelling the idea that any country could target another using genes that are more highly expressed in tissues in people from one ethnic group than others:

(1) ACE2 is also expressed in every other human being on the planet;

(2) ACE2 is expressed in many different tissues, the variation among different ethnic groups is largely unknown.

So, ACE2 variation in the study is not an indication in any way that SARS 2 is expected to more deadly to Asians, or to Asian males.

Further, another study showed that compared to SARS, SARS-2 more weakly binds to ACE2, likely due to conformational differences in the protein that may be reflected in the putative pathogenicity motif signal IPAK has discovered. Our analysis indicates that SARS 2, or at least its spike protein, is an OLDER version of the SARS virus. And while we have not yet ruled out recombination in the wild entirely (although others were quick to rule it out), we have evidence that falsifies the idea that laboratory recombined Spike proteins are in any way involved in the origins of SARS 2.

So, in sum, the very small paper and the underlying knowledge base on the fundamentals of genetics and gene expression patterns cannot be used to support the hypothesis that SARS 2 is engineered to target Asians.

Why Is the Mortality Rate So Low Outside of China?

The current mortality rate outside of China is very low, I estimate around 0.005%, compared to the 2.3% rate in China. Most if not all of the deaths outside of China have involved Chinese citizens who have traveled abroad.

Current hypotheses include that a covert SARS vaccination program was included in the national mandatory vaccination program started on Dec 1, 2019 that happened to involve a secondary true outbreak of Coronavirus with secondary exposure. Under such conditions, the animal models clearly show that vaccination against SARS spike proteins lead to high rates of morbidity and mortality, especially in older mice. No children seem to be dying in China, consistent with them being excluded from a large-scale initial Phase II or Phase III trial. Mortality appears highest in Hubei and Wuhan as well. We know a Phase I trial against SARS was conducted with 120 people by Sinovac around 2007.

Another possibility is that a vaccine used by the Chinese has weakened their response to an otherwise mild coronavirus infection. SARS 2 binding to ACE2 is weaker. Thimerosal inhibits ERAP1. Vaccination with aluminum hydroxide containing vaccines might induce autoimmunity in the lungs. All of these factors could play a role in making vaccinated individuals more susceptible.

A third possibility is that people in that geographic region who had prior SARS infections might be less able to fight off SARS 2 simply due to original antigenic sin from infection. Toronto, Canada, take note.

Either way, as SARS 2 spreads around the world, the medical community should begin to collect past medical exposure information while they collect information on contact w/people who recently traveled to China:

  1. Were you recently vaccinated using aluminum-containing vaccines?
  2. Have you ever received a diagnosis of a SARS infection in the past?
  3. Are you of Asian or Chinese descent?

With these three questions, we could learn a lot about the risk of mortality in a few weeks’ time and plan an informed public health response accordingly.

Also, CDC and WHO should begin to inform owners of public businesses to have their staff wipe down commonly touched spots – door handles, light fixtures, bathroom fixtures, payment keypads, menus – and tell the public to use the Ebola “fist-bump” greeting. People should use their keys or a knuckle to push elevator doors.

These simple, low-cost cultural shifts will reduce the rate of spread of all virus-based disease, including influenza.

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14 thoughts on “More on the ACE2-Related Asian COVID-19 Susceptibility Hypothesis

  1. One of the most telling datapoints within China seems to be the higher mortality rate of male patients. What do you think accounts for the difference in mortality rates between adult males and females?

    Higher rates of smoking in Chinese males is a leading candidate . . . .

  2. asian women suffer high rates of lung disease including cancer as they’ve switched to more western types of cooking oils..why do more boys suffer from autism and kawasaki..boys are subject to vaccine injury at a higher rate than girls..right wrong? can’t say smoking..might be..

  3. One has to wonder why this coronavirus is even newsworthy, when you consider the numbers on the 2 pages below, as well as the population of China vs the U.S.:

    https://www.statista.com/statistics/1090007/china-confirmed-and-suspected-wuhan-coronavirus-cases-region/

    Total of col. 2: 136,552
    Total of col. 3: 3,509

    Pop. of China ~1.4 billion
    Pop. of U.S. ~330 million

    https://www.cdc.gov/flu/about/burden/preliminary-in-season-estimates.htm
    ——
    This is a massive marketing campaign…for God knows what. Given the vaccine research that you have published here, Dr. Weiler, a vaccine for this virus looks very difficult and perhaps undesirable.

    So, what are we being sold?

  4. I think it would be better for you to say [I don’t know].
    Re ACE2, genomic variant by lab-work is already a popular tech, say, there are already patents.

  5. your assumptions are reasonable, but then how do you explain the same evolution of the disease with SARS … at that time there had been no previous infection or vaccination … and the clinical picture in 2003, it seems to me was the same … or are there differences now?
    the footage coming in from China shows strange neurological phenomena … seizures? … are there any opinions on that?

  6. My sincerest apologies for my numbers comment above. The time factor inexplicably dropped out of my mental calculations.

    NPR, yesterday, was pushing a story that this virus came directly from bats. I assume that such bats have been living amongst the Chinese for a very long time. I am pretty certain that I have bats in my attic. I expect there are lots in my neighbor’s barn. I see them flying through my backyard all the time on warm summer nights and am thankful for the amount of bugs that they consume. Bats have been part of my experience in my present house for the last 22 years.

    Am I wrong in thinking that viral pathogenicity is increased in one of 3 ways?:

    1. in laboratories, as a result of scientific effort for a number of reasons, e.g., vaccine research, biowarfare research, pure scientific inquiry…
    2. as a result of environmental pressures, which could include transition to a new host
    3. as a result of host pressures, which could include—in the case of humans—pre-existing illness, malnutrition, stress, exposure to toxins, response to pharmaceuticals…

    I can’t see any reason that bats would be to “blame” for this epidemic. After working hard to try to read Ralph Baric’s paper on biowarfare (Baric is the head of the lab in which Menachery worked), I was disturbed to find that Baric makes it sound almost as though a kid with limited skills and little more than a blender—not meant to be taken literally—could easily create all kinds of nasty viruses these days.

    Am I wrong to think that transition to a new host is the most difficult scenario I’ve enumerated above, and that the biggest factor in all of the equations above is human, in terms of personal health, impact on the environment, and intervention?

  7. If there is a link between the mandatory adult vaccination campaign in China and this outbreak, does anyone know what vaccines those people had, and what their timing was?

  8. A look at the current situation in Italy calls into question any han-genome link. Very high fatality rate here also. Vax rate in Italy also low but recent laws trying to change that.

    1. Makes one wonder, how many of those Italian fatalities could be in fact members of Chinese minority which is huge in Lombardia region? Prato and Milano have their own chinatowns. Actually over a half citizens of Prato are of Chinese descent, from what i read…

  9. Does ACE2 have any bearing on why babies and very young children have a much lower death rate form Covid19? Please refer me to any medical articles on this subject…

  10. There are so many factors.
    Quality of health care received
    Demographics
    Smoking vs non-smoking
    High pollution (China being very polluted)
    I find it pretty impossible to believe this mutated out of bats. Especially not with the Wuhan virology lab sitting right there in Wuhan, which has “studied” coronaviruses. Maybe it came out on somebody’s shoe, but the bat link seems a stretch.
    God bless all sick from this virus.

    1. A significantly higher ACE2 gene expression was found in smoker samples compared to non-smoker samples https://www.preprints.org/manuscript/202002.0051/v1/download

      Up to 68% of Chinese men Smoke whereas only about 2% of Chinese women smoke.
      https://qz.com/521662/68-of-chinese-men-are-smokers-and-millions-will-die-because-of-it/ One third of the world’s smokers live in China. In alveoli, ACE2 is actively expressed in remodelled AT2 cells of former smokers. Together, this study indicates that smokers especially former smokers may be more susceptible to 2019-nCov.

      Northern Italy has the highest rate of lung cancer in Italy, and a high rate of former smokers, from 60% in the 1960s to still 24% smoking in 2017. https://journals.sagepub.com/doi/full/10.5301/tj.5000684 The new york times reported Italy, has the oldest population in Europe, and the second-oldest in the world after Japan. https://www.nytimes.com/2020/03/04/world/europe/coronavirus-italy-elderly.html

      A comparison between eight individual samples had originally demonstrated that the Asian male has an extremely large number of ACE2-expressing cells in the lung and has a much higher ACE2-expressing cell ratio than white and African American donors (2.50% vs. 0.47% of all cells). It should be noted however the asian male in this study was a former smoker- image (FIgure 1). https://www.biorxiv.org/content/10.1101/2020.01.26.919985v1.full

      In Iran, about 20% of the adult male and 4.5% of the adult female population smoke tobacco (12 million smokers according to some estimates). 60,000 Iranians die directly or indirectly due to smoking every year (2008) Smoking is responsible for 25% of deaths in the country. Approx. 54-60 billion cigarettes are believed to be consumed annually in Iran. Iranians spend more than $1.8 billion a year on tobacco https://en.wikipedia.org/wiki/Smoking_in_Iran

      This doesnt include factors such as air pollution or widespread zinc and Vitamin A deficiencies found in China for example.

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