An analysis of the genetic makeup of men under 75 years old reveals that a specific variant of a vital anti-inflammatory gene can shield them from severe illness and death when hospitalized with COVID-19. This gene, known as interleukin-1 receptor antagonist (IL1RN) variant, is thought to reduce the harmful inflammation that the body generates in response to infections, which can sometimes lead to serious conditions like SARS-CoV-2.
A recent study published in The Journal of Infectious Diseases on March 13 discovered that men between 19 and 74 years old carrying the IL1RN variant, specifically the rs419598 variant, had a lower risk of severe illness and an 80% lower chance of dying from COVID-19 after being hospitalized.
The IL1RN gene naturally present in the body can regulate inflammation, a critical function in diseases like arthritis. The study findings suggest that the gene’s influence on inflammation in COVID-19 patients follows a similar pattern. Researchers at NYU Grossman School of Medicine noted a higher mortality rate from COVID-19 among men historically. The IL1RN rs419598 variant appears to offer protective effects for men up to age 74 but not beyond that as age-related diseases become more prevalent.
The research team used advanced sequencing technologies to examine specific gene variants present in blood samples from 258 individuals hospitalized for COVID-19 at NYU Langone’s Tisch Hospital in Manhattan between March 2020 and March 2021. More than half of these patients were over 60 years old and obese, factors associated with higher mortality from the virus. Out of the total patients, 60.5% were men (240) and 39.5% were women (157), with higher numbers of male deaths reported. Women were found to have a 20% lower likelihood of dying from COVID-19 compared to men.
The study also highlighted that despite women generally having a lower mortality rate from COVID-19 than men, men aged 74 and younger who carry the IL1RN gene face a higher mortality risk. The rs419598 variant of the IL1RN gene is connected with lower risks of severe inflammation and death from SARS-CoV-2 infection, as per Dr. Mukundan Attur, a co-lead researcher and molecular biologist at NYU Langone Health.
The study revealed significantly elevated levels of the anti-inflammatory protein IL-1Ra, coded by IL1RN, in both hospitalized men and women when compared to healthy individuals in the general population. In hospitalized men, IL-1Ra levels were 14 times higher, and in hospitalized women, the levels were 10 times higher. However, the research team noted that these increased IL-1Ra levels in women did not lead to a substantial mortality reduction.
The senior investigator, Dr. Steven Abramson, noted a connection between the severe inflammation in SARS-CoV-2 and rheumatoid arthritis. Dr. Abramson, a rheumatologist at NYU Langone, pointed out previous research indicating lower rheumatoid inflammation among individuals with specific IL1 gene variants. The study suggests that targeting the interleukin-1 biological pathway regulated by anti-inflammatory protein IL-1Ra could help alleviate the severe inflammation seen in SARS-CoV-2 infection. Dr. Abramson also advocated for further research to assess the effectiveness of IL-1-inhibiting therapies like anakinra, canakinumab, and rilonacept in combating COVID-19.
Abramson plans to investigate whether the IL-1 pathway plays a role in long COVID, where individuals continue to experience symptoms long after the initial infection. Many COVID-19 survivors report persistent fatigue and cognitive issues even months after recovery from the virus.
This study contributes to the growing body of scientific knowledge on the biological factors underlying the gender disparities in COVID-19 mortality rates, which can vary significantly across different regions of the United States.
Funding for this study was provided by National Institutes of Health grants P30CA016087 and R21AR078466.
Other researchers from NYU Langone involved in the study, in addition to Dr. Abramson and Dr. Attur, include co-lead investigators Dr. Christopher Petrilli and Dr. Samrachana Adhikari, as well as study co-investigator Eduardo Itur.
Reference: Mukundan Attur et al. Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19. The Journal of Infectious Diseases, 2024 DOI: 10.1093/infdis/jiae031