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Genes, Blood Type Tied to Risk of Severe COVID-19

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SARS-CoV-2 virus particles
Caption: Micrograph of SARS-CoV-2 virus particles isolated from a patient.
Credit: National Institute of Allergy and Infectious Diseases, NIH

Many people who contract COVID-19 have only a mild illness, or sometimes no symptoms at all. But others develop respiratory failure that requires oxygen support or even a ventilator to help them recover [1]. It’s clear that this happens more often in men than in women, as well as in people who are older or who have chronic health conditions. But why does respiratory failure also sometimes occur in people who are young and seemingly healthy?

A new study suggests that part of the answer to this question may be found in the genes that each one of us carries [2]. While more research is needed to pinpoint the precise underlying genes and mechanisms responsible, a recent genome-wide association (GWAS) study, just published in the New England Journal of Medicine, finds that gene variants in two regions of the human genome are associated with severe COVID-19 and correspondingly carry a greater risk of COVID-19-related death.

The two stretches of DNA implicated as harboring risks for severe COVID-19 are known to carry some intriguing genes, including one that determines blood type and others that play various roles in the immune system. In fact, the findings suggest that people with blood type A face a 50 percent greater risk of needing oxygen support or a ventilator should they become infected with the novel coronavirus. In contrast, people with blood type O appear to have about a 50 percent reduced risk of severe COVID-19.

These new findings—the first to identify statistically significant susceptibility genes for the severity of COVID-19—come from a large research effort led by Andre Franke, a scientist at Christian-Albrecht-University, Kiel, Germany, along with Tom Karlsen, Oslo University Hospital Rikshospitalet, Norway. Their study included 1,980 people undergoing treatment for severe COVID-19 and respiratory failure at seven medical centers in Italy and Spain.

In search of gene variants that might play a role in the severe illness, the team analyzed patient genome data for more than 8.5 million so-called single-nucleotide polymorphisms, or SNPs. The vast majority of these single “letter” nucleotide substitutions found all across the genome are of no health significance, but they can help to pinpoint the locations of gene variants that turn up more often in association with particular traits or conditions—in this case, COVID-19-related respiratory failure. To find them, the researchers compared SNPs in people with severe COVID-19 to those in more than 1,200 healthy blood donors from the same population groups.

The analysis identified two places that turned up significantly more often in the individuals with severe COVID-19 than in the healthy folks. One of them is found on chromosome 3 and covers a cluster of six genes with potentially relevant functions. For instance, this portion of the genome encodes a transporter protein known to interact with angiotensin converting enzyme 2 (ACE2), the surface receptor that allows the novel coronavirus that causes COVID-19, SARS-CoV-2, to bind to and infect human cells. It also encodes a collection of chemokine receptors, which play a role in the immune response in the airways of our lungs.

The other association signal popped up on chromosome 9, right over the area of the genome that determines blood type. Whether you are classified as an A, B, AB, or O blood type, depends on how your genes instruct your blood cells to produce (or not produce) a certain set of proteins. The researchers did find evidence suggesting a relationship between blood type and COVID-19 risk. They noted that this area also includes a genetic variant associated with increased levels of interleukin-6, which plays a role in inflammation and may have implications for COVID-19 as well.

These findings, completed in two months under very difficult clinical conditions, clearly warrant further study to understand the implications more fully. Indeed, Franke, Karlsen, and many of their colleagues are part of the COVID-19 Host Genetics Initiative, an ongoing international collaborative effort to learn the genetic determinants of COVID-19 susceptibility, severity, and outcomes. Some NIH research groups are taking part in the initiative, and they recently launched a study to look for informative gene variants in 5,000 COVID-19 patients in the United States and Canada.

The hope is that these and other findings yet to come will point the way to a more thorough understanding of the biology of COVID-19. They also suggest that a genetic test and a person’s blood type might provide useful tools for identifying those who may be at greater risk of serious illness.


[1] Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. Wu Z, McGoogan JM, et. al. 2020 Feb 24. [published online ahead of print]

[2] Genomewide association study of severe Covid-19 with respiratory failure. Ellinghaus D, Degenhardt F, et. a. NEJM. June 17, 2020.


The COVID-19 Host Genetics Initiative

Andre Franke (Christian-Albrechts-University of Kiel, Germany)

Tom Karlsen (Oslo University Hospital Rikshospitalet, Norway)

New Study Points to Targetable Protective Factor in Alzheimer’s Disease

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Credit: gettyimages/Creatista

If you’ve spent time with individuals affected with Alzheimer’s disease (AD), you might have noticed that some people lose their memory and other cognitive skills more slowly than others. Why is that? New findings indicate that at least part of the answer may lie in differences in their immune responses.

Researchers have now found that slower loss of cognitive skills in people with AD correlates with higher levels of a protein that helps immune cells clear plaque-like cellular debris from the brain [1]. The efficiency of this clean-up process in the brain can be measured via fragments of the protein that shed into the cerebrospinal fluid (CSF). This suggests that the protein, called TREM2, and the immune system as a whole, may be promising targets to help fight Alzheimer’s disease.

The findings come from an international research team led by Michael Ewers, Institute for Stroke and Dementia Research, Ludwig-Maximilians-Universität München, Germany, and Christian Haass, Ludwig-Maximilians-Universität München, Germany and German Center for Neurodegenerative Diseases. The researchers got interested in TREM2 following the discovery several years ago that people carrying rare genetic variants for the protein were two to three times more likely to develop AD late in life.

Not much was previously known about TREM2, so this finding from a genome wide association study (GWAS) was a surprise. In the brain, it turns out that TREM2 proteins are primarily made by microglia. These scavenging immune cells help to keep the brain healthy, acting as a clean-up crew that clears cellular debris, including the plaque-like amyloid-beta that is a hallmark of AD.

In subsequent studies, Haass and colleagues showed in mouse models of AD that TREM2 helps to shift microglia into high gear for clearing amyloid plaques [2]. This animal work and that of others helped to strengthen the case that TREM2 may play an important role in AD. But what did these data mean for people with this devastating condition?

There had been some hints of a connection between TREM2 and the progression of AD in humans. In the study published in Science Translational Medicine, the researchers took a deeper look by taking advantage of the NIH-funded Alzheimer’s Disease Neuroimaging Initiative (ADNI).

ADNI began more than a decade ago to develop methods for early AD detection, intervention, and treatment. The initiative makes all its data freely available to AD researchers all around the world. That allowed Ewers, Haass, and colleagues to focus their attention on 385 older ADNI participants, both with and without AD, who had been followed for an average of four years.

Their primary hypothesis was that individuals with AD and evidence of higher TREM2 levels at the outset of the study would show over the years less change in their cognitive abilities and in the volume of their hippocampus, a portion of the brain important for learning and memory. And, indeed, that’s exactly what they found.

In individuals with comparable AD, whether mild cognitive impairment or dementia, those having higher levels of a TREM2 fragment in their CSF showed a slower decline in memory. Those with evidence of a higher ratio of TREM2 relative to the tau protein in their CSF also progressed more slowly from normal cognition to early signs of AD or from mild cognitive impairment to full-blown dementia.

While it’s important to note that correlation isn’t causation, the findings suggest that treatments designed to boost TREM2 and the activation of microglia in the brain might hold promise for slowing the progression of AD in people. The challenge will be to determine when and how to target TREM2, and a great deal of research is now underway to make these discoveries.

Since its launch more than a decade ago, ADNI has made many important contributions to AD research. This new study is yet another fine example that should come as encouraging news to people with AD and their families.


[1] Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease. Ewers M, Franzmeier N, Suárez-Calvet M, Morenas-Rodriguez E, Caballero MAA, Kleinberger G, Piccio L, Cruchaga C, Deming Y, Dichgans M, Trojanowski JQ, Shaw LM, Weiner MW, Haass C; Alzheimer’s Disease Neuroimaging Initiative. Sci Transl Med. 2019 Aug 28;11(507).

[2] Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, Nuscher B, Xiong M, Ghasemigharagoz A, Katzmarski N, Krasemann S, Lichtenthaler SF, Müller SA, Colombo A, Monasor LS, Tahirovic S, Herms J, Willem M, Pettkus N, Butovsky O, Bartenstein P, Edbauer D, Rominger A, Ertürk A, Grathwohl SA, Neher JJ, Holtzman DM, Meyer-Luehmann M, Haass C. Nat Neurosci. 2019 Feb;22(2):191-204.


Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)

Alzheimer’s Disease Neuroimaging Initiative (University of Southern California, Los Angeles)

Ewers Lab (University Hospital Munich, Germany)

Haass Lab (Ludwig-Maximilians-Universität München, Germany)

German Center for Neurodegenerative Diseases (Bonn)

Institute for Stroke and Dementia Research (Munich, Germany)

NIH Support: National Institute on Aging

Blast Off! Sending Human Tissue Chips into Space

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Tissue Chips in Space

Credit: Josh Valcarcel, NASA

A big challenge in unlocking the mysteries of aging is how long you need to study humans, or even human cells, to get answers. But, in partnership with NASA, NIH is hoping that space will help facilitate this important area of research.

It’s already known, from what’s been seen in astronauts, that the weightless conditions found in space can speed various processes associated with aging. So, might it be possible to use the space station as a lab to conduct aging experiments?

Can Childhood Stress Affect the Immune System?

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Katie Ehrlich

Katie Ehrlich
Credit: Alan Flurry, University of Georgia, Athens

Whether it’s growing up in gut-wrenching poverty, dealing with dysfunctional family dynamics, or coping with persistent bullying in school, extreme adversity can shatter a child’s sense of emotional well-being. But does it also place kids at higher of developing heart disease, diabetes, and other chronic health conditions as adults?

Katherine Ehrlich, a researcher at University of Georgia, Athens, wants to take a closer look at this question. She recently received a 2018 NIH Director’s New Innovator Award to study whether acute or chronic psychosocial stress during childhood might sensitize the body’s immune system to behave in ways that damage health, possibly over the course of a lifetime.

Creative Minds: Exploring the Role of Immunity in Hypertension

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Meena Madhur

Meena Madhur / Credit: John Russell

If Meena Madhur is correct, people with hypertension will one day pay as much attention to their immune cell profiles as their blood pressure readings. A physician-researcher at Vanderbilt University School of Medicine, Nashville, Madhur is one of a growing number of scientists who thinks the immune system contributes to—or perhaps even triggers—hypertension, which increases the risk of stroke, heart disease, kidney disease, and other serious health problems.

About one of every three adult Americans currently have hypertension, yet a surprising number don’t know they have it and less than half have their high blood pressure under control—leading many health experts to refer to the condition as a “silent killer”[1,2]. For many folks, blood pressure control can be achieved through lifestyle changes, such as losing weight, exercising, limiting salt intake, and taking blood pressure medicines prescribed by their health-care provider. Unfortunately, such measures don’t work for everyone, and some people continue to suffer damage to their kidneys and blood vessels from poorly controlled hypertension.

Madhur wants to know whether the immune system might be playing a role, and whether this might hold some clues for developing new, more targeted ways of treating high blood pressure. To get such answers, this practicing cardiologist will use her 2016 NIH Director’s New Innovator Award to conduct sophisticated, single-cell analyses of the immune systems of people with and without hypertension. Her goal is to produce the most comprehensive catalog to date of which human immune cells might be involved in hypertension.

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