The Stockholm3 blood test, developed by researchers at Karolinska Institutet, is equally effective at detecting prostate cancer in different ethnic groups, according to a new paper published in The Journal of Clinical Oncology. The test produces significantly better results than the current PSA standard.
Stockholm3, a prostate cancer test developed in Sweden, runs a combination of protein and genetic markers from a blood sample through an algorithm to find the probability of a patient having clinically significant cancer.
Studies in more than 90 000 men have shown that Stockholm3 produces significantly better results than the current PSA standard. The test improves prostate cancer diagnosis by reducing unnecessary MRI and biopsies and by identifying significant cancers in men with low or normal PSA values.
Ethnically diverse group
However, previous studies have been conducted primarily in Scandinavia on a mainly White population with uncertain generalisability to the rest of the world. A Swedish-American research group has now examined how well it works in an ethnically mixed group of men in the USA and Canada.
The study included over 2000 men at 17 different clinics, 16% of whom were Asian, 24% African-American, 14% Latin American and 46% White American. All participants had a referral for a prostate biopsy on the basis of an elevated PSA score, abnormal rectal examination, MRI scan or other suspicious clinical finding.
Before the biopsy was performed, a blood test was taken along with clinical data pertinent to the Stockholm3 test, which was conducted blinded to the biopsy results.
Halving the number of unnecessary biopsies
The analysis shows that clinically relevant prostate cancer cases were found in a total of 29% of the men, somewhat more in African Americans and slightly fewer in Asians.
It also shows that the Stockholm3 test could almost halve the number of unnecessary biopsies (45 per cent fewer: 673 as opposed to 1226) while being no less effective at detecting all clinically relevant cases. The results were similar across the different ethnic groups.
“The study demonstrates that the Stockholm3 test is just as effective on an ethnically mixed group as it is on a White, Swedish population,” says the study’s lead author Hari T. Vigneswaran, doctor and PhD student at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
According to him, the research answers several important questions and will lead to a more widespread use of the method:
“Colleagues in other countries are very interested in these data, which show that Stockholm3 works for a non-Swedish population and among minorities.”
Coffee drinking is a heritable habit, and one that carries a certain amount of genetic baggage. Caffeinated coffee is a psychoactive substance, notes Sandra Sanchez-Roige, PhD, an associate professor at University of California San Diego. She is the corresponding author of a study published in the journal Neuropsychopharmacology that compared coffee-consumption characteristics from a 23andMe database in the United States with the UK Biobank.
Lead author Hayley H. A. Thorpe, PhD, at Western University in Ontario, explained that the team collected genetic data as well as self-reported coffee-consumption numbers to assemble a genome-wide association study (GWAS). The idea was to make connections between the genes that were known to be associated with coffee consumption and the traits or conditions related to health.
“We used this data to identify regions on the genome associated with whether somebody is more or less likely to consume coffee,” Thorpe explained. “And then identify the genes and biology that could underlie coffee intake.”
UC San Diego professor Abraham Palmer, PhD is also a lead researcher on the paper. He said that most people are surprised that there is a genetic influence on coffee consumption. “We had good reason to suspect from earlier papers that there were genes that influence how much coffee someone consumes,” he said. “And so, we weren’t surprised to find that in both of the cohorts we examined there was statistical evidence that this is a heritable trait. In other words, the particular gene variants that you inherit from your parents influence how much coffee you’re likely to consume.”
Sanchez-Roige said the genetic influence on coffee consumption was the first of two questions the researchers wanted to address.
“The second is something that coffee lovers are really keen on learning,” Sanchez-Roige said. “Is drinking coffee good or bad? Is it associated with positive health outcomes or not?”
The answer is not definitive. The group’s genome-wide association study of 130 153 U.S.-based 23andMe research participants was compared with a similar UK Biobank database of 334 649 Britons, revealing consistent positive genetic associations between coffee and harmful health outcomes such as obesity and substance use. A positive genetic association is a connection between a specific gene variant (the genotype) and a specific condition (the phenotype). Conversely, a negative genetic association is an apparent protective quality discouraging the development of a condition. The findings get more complicated when it comes to psychiatric conditions.
“Look at the genetics of anxiety, for instance, or bipolar and depression: In the 23andMe data set, they tend to be positively genetically correlated with coffee intake genetics,” Thorpe said. “But then, in the UK Biobank, you see the opposite pattern, where they’re negatively genetically correlated. This is not what we expected.”
She said there were other instances in which the 23andMe set didn’t align with the UK Biobank, but the greatest disagreement was in psychiatric conditions.
“It’s common to combine similar datasets in this field to increase study power. This information paints a fairly clear picture that combining these two datasets was really not a wise idea. And we didn’t end up doing that,” Thorpe said. She explained that melding the databases might mask effects, leading researchers toward incorrect conclusions – or even cancelling each other out.
Sanchez-Roige says the researchers have some ideas about how the differences in results arose. To begin with, there was an apples-and-oranges aspect to the surveys. For instance, the 23andMe survey asked, “How many 5-ounce (cup-sized) servings of caffeinated coffee do you consume each day?” Compare it to the UK Biobank’s “How many cups of coffee do you drink each day? (Include decaffeinated coffee)”
Beyond serving size and the caffeinated/decaf divide, the surveys made no accommodation for the various ways coffee is served. “We know that in the U.K., they have generally higher preference for instant coffee, whereas ground coffee is more preferred in the U.S.,” Thorpe said.
“And then there’s the frappuccinos,” Sanchez-Roige added, citing the American trend of taking coffee loaded with sugary additives. Palmer mentioned other caffeinated drinks and especially in the context of the UK Biobank, tea, none of which were included in the GWAS, which addressed only coffee. Palmer added that the GWAS demonstrates the relationship between genotype and phenotype is more different than the relationship between coffee and tea.
“Genetics influences lots of things. For instance, it influences how tall you might be,” he said. “And those kinds of things probably would play out very similarly, whether you lived in the US or the UK But coffee is a decision that people make.”
Sanchez-Roige pointed out that coffee comes in a variety of forms, from instant to frappuccino, and is consumed amid cultural norms that differ from place to place. A person with a given genotype might end up having quite a different phenotype living in the UK versus the US.
“And that’s really what the data are telling us,” she said. “Because unlike height, where your behaviour doesn’t really have much to do with it, your behaviour and the choices you’re making in your environment play out in various ways. So the interaction between genotype and environment complicates the picture.”
The collaborators stressed the need for more investigation to unravel the relationships between genetics and the environment, focusing not only on coffee/caffeine intake but also other substance-use issues.
Researchers have identified inherited genetic variants that may predict the loss of one copy of a woman’s two X chromosomes as she ages, a phenomenon known as mosaic loss of chromosome X, or mLOX. These genetic variants may play a role in promoting abnormal blood cells (that have only a single copy of chromosome X) to multiply, which may lead to several health conditions, including cancer. The study, co-led by researchers at the National Cancer Institute, part of the National Institutes of Health, was published in Nature.
To better understand the causes and effects of mLOX, researchers analysed circulating white blood cells from nearly 900 000 women across eight biobanks, of whom 12% had the condition. The researchers identified 56 common genetic variants – located near genes associated with autoimmune diseases and cancer susceptibility – that influenced whether mLOX developed. In addition, rare variants in a gene known as FBXO10 were associated with a doubling in the risk of mLOX.
In women with mLOX, the investigators also identified a set of inherited genetic variants on the X chromosome that were more frequently observed on the retained X chromosome than on the one that was lost. These variants could one day be used to predict which copy of the X chromosome is retained when mLOX occurs. This is important because the copy of the X chromosome with these variants may have a growth advantage that could elevate the woman’s risk for blood cancer.
The researchers also looked for associations of mLOX with more than 1,200 diseases and confirmed previous findings of an association with increased risk of leukemia and susceptibility to infections that cause pneumonia.
The scientists suggest that future research should focus on how mLOX interacts with other types of genetic variation and age-related changes to potentially alter disease risk.
Novel enEbCas12a protein shows potential promise as gene-editing tool to one day treat disease
Researchers have developed a novel version of a key CRISPR gene-editing protein that shows efficient editing activity and is small enough to be packaged within a non-pathogenic virus that can deliver it to target cells. Hongjian Wang and colleagues at Wuhan University, China, present these findings May 30th in the open-access journal PLOS Biology.
Recent years have seen an explosion of research attempting to harness CRISPR gene-editing systems – which are found naturally in many bacteria as a defence against viruses – so they can be used as potential treatments for human disease. These systems rely on so-called CRISPR-associated (Cas) proteins, with Cas9 and Cas12a being the two most widely used types, each with their own quirks and strengths.
One promising idea is to package CRISPR proteins within a non-pathogenic virus, which could then deliver the proteins to target cells; there, they would modify specifically targeted DNA sequences to treat disease. However, the commonly used adeno-associated virus is small, and while some Cas9 proteins can fit inside, Cas12a proteins are typically too large.
Now, Wang and colleagues have identified a relatively small version of Cas12a, termed EbCas12a, that occurs naturally in a species of the Erysipelotrichia class of bacteria. By deliberately switching out one of the amino acid building blocks of the protein for another, they boosted its gene-editing efficiency. When applied to mammalian cells in a dish in the lab, this modified protein—dubbed enEbCas12a—shows gene-editing efficiency comparable to that of two other Cas12a proteins known for highly accurate gene editing.
The research team then demonstrated that enEbCas12a is small enough to be used for adeno-associated virus-based gene therapy. They modified enEbCas12a to target a specific cholesterol-associated gene, packaged it within the virus, and administered the virus to mice with high cholesterol. One month later, they found a significant reduction of blood cholesterol levels in the treated mice, compared to mice that did not receive the virus.
More research will be needed to determine if enEbCas12a could one day be used to address human disease. Nonetheless, these findings suggest it could be possible to use adeno-associated virus to deliver Cas12a proteins for gene therapy.
The authors add, “The novel compact enEbCas12a, along with its crRNA, can be packaged into an all-in-one AAV system for convenient gene editing in vitro and in vivo with high-fidelity, which can be very beneficial for future clinical applications and more tool developments including all-in-one AAV- based multi-gene editing, base editing, primer editing, etc.”
About 79% of clinical trial participants experienced measurable improvement after receiving experimental, CRISPR-based gene editing that is designed to fix a rare form of blindness, according to a paper published in the New England Journal of Medicine.
“This trial shows CRISPR gene editing has exciting potential to treat inherited retinal degeneration,” said corresponding author Mark Pennesi, MD, PhD. “There is nothing more rewarding to a physician than hearing a patient describe how their vision has improved after a treatment. One of our trial participants has shared several examples, including being able to find their phone after misplacing it and knowing that their coffee machine is working by seeing its small lights.
Pennesi is an ophthalmologist and Oregon Health & Science University’s lead scientist for the Phase 1/2 BRILLIANCE trial, which evaluated the safety and effectiveness of EDIT-101, an experimental CRISPR-based gene editing treatment developed by Editas Medicine. The experimental treatment was designed to edit a mutation in the CEP290 gene, which provides instructions to create a protein that is critical for sight.
People with this gene mutation have a rare condition that is commonly called Leber Congenital Amaurosis, or LCA, Type 10, for which there is currently no Food and Drug Administration-approved treatment. LCA’s various types occur in about 2 or 3 out of 100 000 newborns.
The OHSU Casey Eye Institute treated the trial’s first participant in early 2020. That procedure also marked the first time that CRISPR had been used to edit genes within the human body, called in vivo gene editing.
The new paper describes the study’s findings through February 2023 and details how the trial’s 14 participants – 12 adults and two children – responded to receiving EDIT-101 in one eye. Key results include:
11 participants, about 79%, showed improvement in at least one of four measured outcomes.
6 participants, about 43%, showed improvement in two or more outcomes.
6 participants, about 43%, reported improved vision-related quality of life.
4 participants, about 29%, had clinically meaningful improvement in visual acuity, or how well they could identify objects or letters on a chart.
There were no serious adverse events related to the treatment.
Most adverse events were mild or moderate, and all have since been resolved.
Four specific outcomes were used to evaluate the experimental treatment’s effectiveness:
Visual acuity
How well participants did in a full-field test, which involves seeing coloured points of light while looking into a specialised device
How well participants navigated a research maze with physical objects and varying amounts of light
How much participants reported experiencing improved quality of life
Further research for a future treatment
In November 2022, trial sponsor Editas Medicine announced that it was pausing the trial’s enrolment and would seek another partner to continue the experimental therapy’s development. Pennesi and colleagues are exploring working with other commercial partners to conduct additional trials, in collaboration with Editas. The researchers hope future studies can examine ideal dosing, whether a treatment effect is more pronounced in certain age groups such as younger patients, and include refined endpoints to measure impacts on activities of daily living.
A group of researchers at the University of California San Diego School of Medicine led an investigation that offers new insight into the causes of spina bifida, the most common structural disorder of the human nervous system.
The group’s work reveals the first link between spina bifida and a common chromosomal microdeletion in humans. The study demonstrates that individuals carrying this chromosomal deletion – present in one of 2500 live births – demonstrate a risk of spina bifida more than 10 times greater than the general public.
The study, published in Science, also underscores the potential role of folic acid (aka vitamin B-9) in reducing the risk of spina bifida.
Professor Joseph G. Gleeson at Rady Children’s Institute for Genomic Medicine, is the senior author of the study. He explained that spina bifida, also known as meningomyelocele, affects one in every 3000 newborns. Unfortunately, the causes are mostly unknown. A few mutations were reported but could only explain a tiny fraction of risk, Gleeson added.
To uncover the genetic causes of the disease, Gleeson’s UC lab joined with colleagues around the world to establish the Spina Bifida Sequencing Consortium in 2015. The consortium began focusing on a tiny deletion in chromosome 22. Chromosome microdeletions refer to a condition in which several genes in a chromosome are missing. The group’s target condition, known as 22q11.2del, has been implicated in a number of other disorders. They began looking for 22q11.2del in spinal bifida patients.
“All patients we recruited have the most severe form of spina bifida, and all underwent best-practice comprehensive genomic sequencing,” Gleeson said. “We identified 22q11.2del in 6 out of 715 patients. This may not seem a high percentage, but this is by far the most common single genetic variation that could contribute to spina bifida.”
He went on to say the group identified eight additional spina bifida patients who carried the deletion from a cohort of approximately 1500 individuals recruited because of the presence of the common 22q11.2 deletion, Gleeson said.
The researchers then narrowed the cause among the many genes in the 22q11.2 deletion to a single gene known as CRKL. Gleeson explained that there are nine other genes in this chromosomal region that could have been the cause. He said the team began a process of elimination, “knocking out” each of the mouse genes one-by-one, when they received a fortuitous email from Dolores Lamb from Weil Cornell College of Medicine. Lamb had noted some of the mice in their vivarium that were missing Crkl and showed spina bifida. (Study co-first author Keng Ioi Vong, PhD, explained that researchers use all capital letters to describe the gene in humans, and lower-case for mice.) Lamb’s group heard about the Gleeson lab project through the Spina Bifida Association.
“This finding really got us excited because it meant that CRKL disruption might be sufficient for spina bifida,” said Vong. “We removed the mouse Crkl gene ourselves and confirmed that some of the mice developed neural tube defects, including spina bifida.” Most of the other genes in 22q11.2 deletion were subsequently excluded, he added.
They next turned their attention to how folic acid may modulate CRKL-mediated spina bifida. Vong noted that prior studies in humans demonstrated that folic acid supplementation prior to conception reduces the incidence of spina bifida and other neural tube defects by up to 30-50 %, but the mechanisms are still a mystery.
“When we deprived the Crkl mutant female mice of folic acid in their chow, many more of their offspring had neural tube defects, and the severity increased dramatically,” Vong explained. “This suggests that folic acid taken by pregnant women may not only reduce the risk, but also the severity of neural tube defects in their offspring.”
“We hope our findings can help the research community to better understand causes of neural tube defects, especially the causes attributable to common genetic findings like 22q11.2 deletion,” Gleeson said. “We also hope our findings can contribute to healthy pregnancies, improved women’s health, and improved outcomes for children.”
Researchers in Japan discovered that a special kind of genetic mutation works differently from typical mutations in how it contributes to autism spectrum disorder (ASD). In essence, because of the three-dimensional structure of the genome, mutations are able to affect neighbouring genes that are linked to ASD, thus explaining why ASD can occur even without direct mutations to ASD-related genes. This study appeared in the scientific journal Cell Genomics.
ASD is a group of conditions characterised in part by repetitive behaviours and difficulties in social interaction. Although it runs in families, the genetics of its heritability are complex and remain only partially understood. Studies have shown that the high degree of heritability cannot be explained simply by looking at the part of the genome that codes for proteins. Rather, the answer could lie in the non-coding regions of the genome, particularly in promoters, the parts of the genome that ultimately control whether or not the proteins are actually produced. The team led by Atsushi Takata at in the RIKEN Center for Brain Science (CBS) examined de novo gene variants (new, non-inherited mutations) in these parts of the genome.
The researchers analysed an extensive dataset of over 5000 families, making this one of the world’s largest genome-wide studies of ASD to date. They focused on TADs – three-dimensional structures in the genome that allow interactions between different nearby genes and their regulatory elements. They found that de novo mutations in promoters heightened the risk of ASD only when the promoters were located in TADs that contained ASD-related genes. Because they are nearby and in the same TAD, these de novo mutations can affect the expression of ASD-related genes. In this way, the new study explains why mutations can increase the risk of ASD even when they aren’t located in protein-coding regions or in the promotors that directly control the expression of ASD-related genes.
“Our most important discovery was that de novo mutations in promoter regions of TADs containing known ASD genes are associated with ASD risk, and this is likely mediated through interactions in the three-dimensional structure of the genome,” says Takata.
To confirm this, the researchers edited the DNA of stem cells using the CRISPR/Cas9 system, making mutations in specific promoters. As expected, they observed that a single genetic change in a promotor caused alterations in an ASD-associated gene within the same TAD. Because numerous genes linked to ASD and neurodevelopment were also affected in the mutant stem cells, Takata likens the process to a genomic “butterfly effect” in which a single mutation dysregulates disease-associated genes that are scattered in distant regions of the genome.
Takata believes that this finding has implications for the development of new diagnostic and therapeutic strategies. “At the very least, when assessing an individual’s risk for ASD, we now know that we need to look beyond ASD-related genes when doing genetic risk assessment, and focus on whole TADs that contain ASD-related genes,” explains Takata. “Further, an intervention that corrects aberrant promoter-enhancer interactions caused by a promotor mutation may also have therapeutic effects on ASD.”
Further research involving more families and patients is crucial for better understanding ASD’s genetic roots. “By expanding our research, we will gain a better understanding of the genetic architecture and biology of ASD, leading to clinical management that enhances the well-being of affected individuals, their families, and society,” says Takata.
NIH-led study finds genetic markers that explain up to 12% of the differences between two people’s blood pressure.
Photo by CDC on Unsplash
National Institutes of Health researchers and collaborators have discovered over 100 new regions of the human genome, also known as genomic loci, that appear to influence a person’s blood pressure. Results of the study also point to several specific genomic loci that may be relevant to iron metabolism and a type of cellular receptor known as adrenergic receptors.
The study, published in Nature Genetics, is one of the largest such genomic studies of blood pressure to date, including data from over 1 million participants and laying the groundwork for researchers to better understand how blood pressure is regulated. Such insights could point to potential new drug targets.
“Our study helps explain a much larger proportion of the differences between two people’s blood pressure than was previously known,” said first author Jacob Keaton, PhD. “Our study found additional genomic locations that together explain a much larger part of the genetic differences in people’s blood pressure. Knowing a person’s risk for developing hypertension could lead to tailored treatments, which are more likely to be effective.”
Hypertension often runs in families, meaning that there is a genetic component to developing the condition in addition to environmental contributions such as a high-salt diet, lack of exercise, smoking and stress.
To understand the genetics of blood pressure, the researchers combined four large datasets from genome-wide association studies of blood pressure and hypertension. After analysing the data, they found over 2000 genomic loci linked to blood pressure, including 113 new regions. Among the newly discovered genomic loci, several reside in genes that play a role in iron metabolism, confirming previous reports that high levels of accumulated iron can contribute to cardiovascular disease.
The researchers also confirmed the association between variants in the ADRA1A gene and blood pressure. ADRA1A encodes a type of cell receptor, called an adrenergic receptor, that is currently a target for blood pressure medication, suggesting that other genomic variants discovered in the study may also have the potential to be drug targets to alter blood pressure.
“This study shows that these big genome-wide association studies have clinical relevance for finding new drug targets and are needed to discover more drug targets as we go forward,” said Dr Keaton.
From these analyses, the researchers were able to calculate a polygenic risk score, which combines the effects of all genomic variants together to predict blood pressure and risk for hypertension. These risk scores consider which genomic variants confer risk for hypertension and reveal clinically meaningful differences between people’s blood pressure.
Polygenic risk scores have potential to serve as a useful tool in precision medicine, but more diverse genomic data is needed for them to be applicable broadly in routine health care. While the collected data was mostly from people of European ancestry, the polygenic risk scores were also applicable to people of African ancestry.
People with a rare longevity condition known as growth hormone receptor deficiency (GHRD) may also have possible cardiovascular health advantages. Also called Laron syndrome, GHRD, which is characterised by the body’s impaired ability to use its own growth hormone and results in stunted growth, has been linked in mice to a record 40% longevity extension and lower risks for various age-related diseases.
The risk of cardiovascular disease in individuals with GHRD has remained unclear until now, leading to the speculation that in people, this mouse longevity mutation may actually increase cardiovascular disease. In humans, unlike mice, GHRD is not associated with an extended lifespan.
The study, appearing in Med, is the latest product of an international collaboration spanning nearly 20 years between Valter Longo, professor of gerontology at the USC Leonard Davis School of Gerontology, and endocrinologist Jaime Guevara-Aguirre of the Universidad San Francisco de Quito, Ecuador.
Over the past two decades, Longo, Guevara-Aguirre and colleagues have examined the health and aging of people with the gene mutation that causes GHRD. This rare mutation, found in just 400 to 500 people worldwide, was identified in a group of Ecuadorians whose ancestors had fled Spain during the Inquisition more than three centuries ago. The mutation leaves them with ineffective growth hormone receptors and results in a type of dwarfism.
The team’s previous research has indicated that while GHRD/Laron syndrome reduces growth, it also appears to reduce the risk of several age-related diseases. Although the Ecuadorians with GHRD have a higher rate of obesity, they have a very low risk of cancer and Type 2 diabetes. They also appear to have healthier brains and better performance on tests of cognition and memory.
For the current study, the research team examined cardiovascular function, damage, and risk factors in GHRD subjects and their relatives. Researchers conducted two phases of measurements in Los Angeles and Ecuador, involving a total of 51 individuals, with 24 diagnosed with GHRD and 27 relatives without GHRD serving as controls.
Key findings from the study included:
GHRD subjects displayed lower blood sugar, insulin resistance, and blood pressure compared to the control group.
They also had smaller heart dimensions and similar pulse wave velocity (a measure of stiffness in the arteries) but had lower carotid artery thickness compared to control subjects.
Despite elevated low-density lipoprotein (LDL) levels, GHRD subjects showed a trend for lower carotid artery atherosclerotic plaques compared to controls (7% vs 36%).
“These findings suggest that individuals with GHRD have normal or improved levels of cardiovascular disease risk factors compared to their relatives,” said Longo, senior author of the new study. “Although the population tested is small, together with studies in mice and other organisms this human data provide valuable insights into the health effects of growth hormone receptor deficiency and suggest that drugs or dietary interventions that cause similar effects could reduce disease incidence and possibly extend longevity.”
A certain variant of a key anti-inflammatory gene protects men under age 75 from severe illness and death when hospitalised from COVID, a genetic analysis of their blood shows. According to the authors of a major study published in The Journal of Infectious Diseases, the protective gene in question, an interleukin-1 receptor antagonist (IL1RN) variant, appears to tamp down inflammation, which can get out of control in severe cases SARS-CoV-2 infection.
The study showed that 124 men between the ages of 19 and 74 who possessed the IL1RN variant, called rs419598, were less likely to become severely ill after hospitalisation for COVID, and 80% less likely to die from the disease.
IL1RN is expressed naturally in the body. Different types of interleukin genes are known to dial inflammation up or down in the context of arthritis, and researchers say the results of the current study suggest that a similar dynamic influences the interleukin-1-related inflammation seen in COVID patients.
The findings, from researchers at NYU Grossman School of Medicine, stand out because historically more men than women are known to die from COVID, and the IL1RN rs419598 variant appears to selectively protect only men up to age 74, but not beyond that as age-related chronic illnesses unfold.
The research team used sequencing technologies for the study to determine the presence of specific genes or variations in the letter code that makes up genes in blood samples from 2589 men and women hospitalised for COVID at NYU Langone’s Tisch Hospital in Manhattan from March 2020 to March 2021.
More than half of the men and women in the study were older than age 60 and obese, factors that are known to increase the risk of death from the viral infection. Overall, more men than women (240 men, at 60.5%; and 157 women, at 39.5%) died from their disease, with women 20% less likely to die than men.
“Our study results show that among hospitalised patients, while women are still overall less likely than men to die from COVID-19, those men age 74 and younger who possess the IL1RN gene variant rs419598 are much less likely to suffer the severe inflammation tied to SARS-CoV-2 infection and less likely to die from the disease,” said study colead investigator and molecular biologist Mukundan Attur, PhD. Attur is an associate professor in the Department of Medicine at NYU Langone Health.
Among the study’s other findings was that average blood levels of the anti-inflammatory protein IL-1Ra, coded by IL1RN, were 14 times higher in 181 hospitalised men than in healthy male study controls from the general population, and 10 times as high in 178 hospitalised women than in healthy females. The increased levels of IL-1Ra in women did not result in any statistically significant mortality reductions.
“Our analysis offers substantial evidence of the biological link between the severe inflammation seen in SARS-CoV-2 and that which occurs in rheumatoid arthritis,” said study senior investigator Steven Abramson, MD, the Frederick H. King Professor of Internal Medicine at NYU Langone.
Abramson, a rheumatologist who also serves as chair of the Department of Medicine and chief academic officer at NYU Langone, says previous research has shown that such rheumatoid inflammation is lower in people who possessed one of the three IL1RN variants analysed in the study.
More importantly, Abramson says, the new research suggests that restraining the interleukin-1 biological pathway, which is in part tamped down by the anti-inflammatory protein IL-1Ra, could help prevent the severe inflammation seen in SARS-CoV-2 infection. Further research, he says, is warranted into whether IL-1-inhibiting therapies, such as the IL1 receptor antagonists anakinra, canakinumab, and rilonacept, are effective against Covid infection.
Abramson already has plans to investigate if the IL-1 pathway plays a role in long Covid, when people experience new or lingering symptoms, such as fatigue and ‘brain fog’, months after recuperating from their initial infection.
Abramson points out that the new study adds to the growing scientific evidence about the biological factors that contribute to gender differences seen in deaths from COVID, which are known to vary widely across the United States.
