What is the genetic influence on the severity of COVID-19?


A striking characteristic of COVID-19 is that the severity of clinical outcomes is remarkably variable. Establishing a prognosis for individuals infected with COVID-19 remains a challenge.

Since the start of the COVID-19 pandemic, the heterogeneity of individuals who progress toward severe disease or death, along with the fact that individuals directly exposed to the virus do not necessarily become sick, supports the hypothesis that genetic risk or protective factors are at play.

In an interview with this news organization, Mayana Zatz, PhD, head professor of genetics and coordinator of the Human Genome and Stem Cell Study Center at the University of São Paulo, explained: “The first case that caught my eye was the case of my neighbors, a couple. He presented COVID-19 symptoms, but his wife, who took care of him, had absolutely no symptoms. I thought that it was strange, but we received 3,000 emails from people saying, ‘This happened to me, too.’”

Reports in the media about seven pairs of monozygotic (MZ) twins who died from COVID-19 within days of one another in Brazil also stood out, said the researcher.

Twin studies are important for investigating the contribution of genetics vs. that of the environment in the susceptibility or resistance to infectious diseases, as well as their pathology. Dr. Zatz’s team analyzed the case of a 31-year-old Brazilian MZ twin brother pair who presented simultaneously with severe COVID-19 and the need for oxygen support, despite their age and good health conditions. Curiously, they were admitted and intubated on the same day, but neither of the twins knew about the other’s situation; they found out only when they were extubated.

The study was carried out at the USP with the collaboration of the State University of São Paulo. The authors mapped the genetic profile (by sequencing the genome responsible for coding proteins, or whole-exome sequencing) and the immune cell profile to evaluate innate and adaptive immunity.

The MZ twin brothers shared the same two rare genetic mutations, which may be associated with their increased risk of developing severe COVID-19. However, since these variants were not studied at the protein or functional level, their pathogenicity has yet to be determined. The twins also had [human leukocyte antigen (HLA)] alleles associated with severe COVID-19, which are important candidates for the mechanisms of innate and adaptive immunity and susceptibility to COVID-19 infection and manifestation.

But one particular oddity stood out to the researchers: One of the brothers required longer hospitalization, and only he reported symptoms of long COVID.

In the authors’ eyes, even though the patients shared genetic mutations potentially associated with the risk of developing severe COVID-19, the differences in clinical progression emphasize that, beyond genetic risk factors, continuous exposure to pathogens over a lifetime and other environmental factors mean that each individual’s immune response is unique, even in twins.

“There is no doubt that genetics contribute to the severity of COVID-19, and environmental factors sometimes give us the opportunity to study the disease, too. Such [is the case with] MZ twins who have genetic similarities, even with changes that take place over a lifetime,” José Eduardo Krieger, MD, PhD, professor of molecular medicine at the University of São Paulo Medical School (FMUSP), told this news organization. “Examining MZ twins is a strategy that may help, but, with n = 2, luck really needs to be on your side to get straight to the problem. You need to combine [these findings] with other studies to solve this conundrum,” said Dr. Krieger, who did not take part in the research.


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