Gene variant provides clue for why some men were less severely ill from COVID
The study, in which Dr. Steven Abramson of NYU Langone Health was the senior investigator, found men under 75 with the variant hospitalized with COVID were 80% less likely to die than those without the variant. Credit: NYU Langone Health /Joshua Bright
Men with a particular gene variant are far less likely to get severely ill and die of COVID-19, a newly released study found, and researchers say the conclusions could lead to strategies to help others also better fight active COVID-19 infections, and to reduce the effects of long COVID.
The gene variant, rs419598, helps regulate the number of anti-inflammatory molecules that are produced, said Dr. Steven Abramson, the study’s senior investigator and chair of medicine at NYU Langone Health.
Men under 75 years old with the variant who were hospitalized with COVID-19 were 80% less likely to die than those without the variant, the study found. The mortality rate among them was 3.1%, compared with 14% for men under 75 without the variant.
But the study found the gene variant did not provide additional protection for women, for reasons that aren’t entirely clear, although researchers said they may be related to "poorly understood sex differences" in inflammatory responses as a whole. Overall, men are more likely than women to die from COVID-19.
The blood of 2,589 COVID-19 patients hospitalized at NYU Langone’s Tisch Hospital in Manhattan between March 2020 and March 2021 was analyzed for the study, published Wednesday in The Journal of Infectious Diseases.
Anti-inflammatory molecules are key, because “excessive inflammation is probably the most important feature of severe COVID that is causing people to do poorly,” Abramson said.
Inflammation is part of the immune system’s response to COVID-19. The virus “activates cells that are ordinarily there to protect you,” Abramson said.
“But when you get what's called hyper-inflammation, the cells overreact to the virus,” he said.
Inflammatory molecules released by cells cause damage to tissues and can, for example, cause lungs to fail, he said.
“If we can control the inflammation, we can control the disease,” said Mukundan Attur, a co-lead investigator of the study and an associate professor of medicine at the NYU Langone Grossman School of Medicine who, like Abramson, is a rheumatologist. Previous research by Attur and Abramson showed the gene variant can reduce symptoms of rheumatoid arthritis and osteoarthritis.
The rs419598 gene variant “helps dampen the damage caused by the inflammation …,” Abramson said. “If you have this gene, you make more of [an] anti-inflammatory protein.”
Previous studies also have found links between genes and COVID-19 severity. One study published in July in the journal Nature found that another gene variant was about twice as common in people who had COVID-19 without symptoms than in those who had COVID-19 with symptoms. Another study, from 2022, published in Cell Systems, found more than 1,000 genes associated with people who had severe COVID-19 disease.
The gene variant is present only in about 7% to 8% of people, and in fewer than 1% of those with African ancestry, researchers said.
But the study’s findings could help provide a road map to helping others with acute COVID-19 and people with long COVID, which are the long-term effects of the virus, Abramson said.
In addition to identifying the protective role of rs419598, the study also shows there should be more focus in research on better regulating the activation of a series of signals — called “pathways ‘’ — that tell cells to produce inflammatory molecules, he said. Tamping down those signals could reduce the severity of COVID-19, he said.
Mark Heise, a professor of genetics, microbiology and immunology at the University of North Carolina at Chapel Hill, who was not involved with the new study, said the new research helps scientists better understand those pathways. Other studies also have found associations between the pathways and the severity of COVID-19 disease, he said.
“The better we understand those pathways, the more targeted we can be with interventions,” he said.
Steroids like dexamethasone have helped reduce inflammation in COVID-19 patients, he said. But more targeted therapy could be more effective, he said.
“If we could tailor the therapy to be even more specific, it has potential benefits from a clinical standpoint" in blocking the harmful aspects of inflammation while maintaining the positive ones, Heise said. “So that would be what I would view as a long-term goal of these sorts of studies.”
Abramson and Attur currently are researching whether the gene variant influences whether someone has long COVID, and the severity of long COVID. They’ve already found that although many long COVID patients have chronic inflammation, “their blood is less inflamed when they have the gene” rs419598, Abramson said.
Researchers are still analyzing data on whether long COVID in those with the variant is less severe or less long-lasting, he said.
Men with a particular gene variant are far less likely to get severely ill and die of COVID-19, a newly released study found, and researchers say the conclusions could lead to strategies to help others also better fight active COVID-19 infections, and to reduce the effects of long COVID.
The gene variant, rs419598, helps regulate the number of anti-inflammatory molecules that are produced, said Dr. Steven Abramson, the study’s senior investigator and chair of medicine at NYU Langone Health.
Men under 75 years old with the variant who were hospitalized with COVID-19 were 80% less likely to die than those without the variant, the study found. The mortality rate among them was 3.1%, compared with 14% for men under 75 without the variant.
But the study found the gene variant did not provide additional protection for women, for reasons that aren’t entirely clear, although researchers said they may be related to "poorly understood sex differences" in inflammatory responses as a whole. Overall, men are more likely than women to die from COVID-19.
WHAT TO KNOW
NYU Langone Health researchers identified a gene variant that dramatically reduced the rate of death of men under 75 who were hospitalized for COVID-19, a newly released study shows.
The variant helps regulate the number of anti-inflammatory molecules that are produced. That is key because excess inflammation is associated with severe COVID-19 disease and death.
Only about 7% to 8% of the population carries the gene variant. But the study’s findings may help researchers develop strategies to better help people with acute COVID and long COVID.
The blood of 2,589 COVID-19 patients hospitalized at NYU Langone’s Tisch Hospital in Manhattan between March 2020 and March 2021 was analyzed for the study, published Wednesday in The Journal of Infectious Diseases.
Anti-inflammatory molecules are key, because “excessive inflammation is probably the most important feature of severe COVID that is causing people to do poorly,” Abramson said.
Inflammation is part of the immune system’s response to COVID-19. The virus “activates cells that are ordinarily there to protect you,” Abramson said.
“But when you get what's called hyper-inflammation, the cells overreact to the virus,” he said.
Inflammatory molecules released by cells cause damage to tissues and can, for example, cause lungs to fail, he said.
“If we can control the inflammation, we can control the disease,” said Mukundan Attur, a co-lead investigator of the study and an associate professor of medicine at the NYU Langone Grossman School of Medicine who, like Abramson, is a rheumatologist. Previous research by Attur and Abramson showed the gene variant can reduce symptoms of rheumatoid arthritis and osteoarthritis.
“If we can control the inflammation, we can control the disease," said Mukundan Attur, a co-lead investigator in the study. Credit: NYU Langone Health
The rs419598 gene variant “helps dampen the damage caused by the inflammation …,” Abramson said. “If you have this gene, you make more of [an] anti-inflammatory protein.”
Previous studies also have found links between genes and COVID-19 severity. One study published in July in the journal Nature found that another gene variant was about twice as common in people who had COVID-19 without symptoms than in those who had COVID-19 with symptoms. Another study, from 2022, published in Cell Systems, found more than 1,000 genes associated with people who had severe COVID-19 disease.
The gene variant is present only in about 7% to 8% of people, and in fewer than 1% of those with African ancestry, researchers said.
But the study’s findings could help provide a road map to helping others with acute COVID-19 and people with long COVID, which are the long-term effects of the virus, Abramson said.
In addition to identifying the protective role of rs419598, the study also shows there should be more focus in research on better regulating the activation of a series of signals — called “pathways ‘’ — that tell cells to produce inflammatory molecules, he said. Tamping down those signals could reduce the severity of COVID-19, he said.
Mark Heise, a professor of genetics, microbiology and immunology at the University of North Carolina at Chapel Hill, who was not involved with the new study, said the new research helps scientists better understand those pathways. Other studies also have found associations between the pathways and the severity of COVID-19 disease, he said.
“The better we understand those pathways, the more targeted we can be with interventions,” he said.
Steroids like dexamethasone have helped reduce inflammation in COVID-19 patients, he said. But more targeted therapy could be more effective, he said.
“If we could tailor the therapy to be even more specific, it has potential benefits from a clinical standpoint" in blocking the harmful aspects of inflammation while maintaining the positive ones, Heise said. “So that would be what I would view as a long-term goal of these sorts of studies.”
Abramson and Attur currently are researching whether the gene variant influences whether someone has long COVID, and the severity of long COVID. They’ve already found that although many long COVID patients have chronic inflammation, “their blood is less inflamed when they have the gene” rs419598, Abramson said.
Researchers are still analyzing data on whether long COVID in those with the variant is less severe or less long-lasting, he said.
David Olson covers health care. He has worked at Newsday since 2015 and previously covered immigration, multicultural issues and religion at The Press-Enterprise in Southern California.
