Accelerating gains in abdominal fat during menopause tied to heart disease risk

heart

Women who experience an accelerated accumulation of abdominal fat during menopause are at greater risk of heart disease, even if their weight stays steady, according to a University of Pittsburgh Graduate School of Public Health-led analysis published today in the journal Menopause.

The study—based on a quarter century of data collected on hundreds of women—suggests that measuring waist circumference during preventive health care appointments for midlife women could be an early indicator of heart disease risk beyond the widely used body mass index (BMI)—which is a calculation of weight vs. height.

“We need to shift gears on how we think about heart disease risk in women, particularly as they approach and go through menopause,” said senior author Samar El Khoudary, Ph.D., M.P.H., associate professor of epidemiology at Pitt Public Health. “Our research is increasingly showing that it isn’t so important how much fat a woman is carrying, which doctors typically measure using weight and BMI, as it is where she is carrying that fat.”

El Khoudary and her colleagues looked at data on 362 women from Pittsburgh and Chicago who participated in the Study of Women’s Health Across the Nation (SWAN) Heart study. The women, who were an average age of 51, had their visceral adipose tissue—fat surrounding the abdominal organs—measured by CT scan and the thickness of the internal carotid artery lining in their neck measured by ultrasound, at a few points during the study. Carotid artery thickness is an early indicator of heart disease.

The team found that for every 20% increase in abdominal fat, the thickness of the carotid artery lining grew by 2% independent of overall weight, BMI and other traditional risk factors for heart disease.

They also found that abdominal fat started a steep acceleration, on average, within two years before the participants’ last period and continued a more gradual growth after the menopausal transition.

Saad Samargandy, Ph.D., M.P.H., who was a doctoral student at Pitt Public Health at the time of the research, explained that fat that hugs the abdominal organs is related to greater secretion of toxic molecules that can be harmful to cardiovascular health.

“Almost 70% of post-menopausal women have central obesity—or excessive weight in their mid-section,” said Samargandy, also the first author of the journal article. “Our analysis showed an accelerated increase of visceral abdominal fat during the menopausal transition of 8% per year, independent of chronological aging.”

Measuring abdominal fat by CT scan is expensive, inconvenient and could unnecessarily expose women to radiation—so El Khoudary suggests that regularly measuring and tracking waist circumference would be a good proxy to monitor for accelerating increases in abdominal fat. Measuring weight and BMI alone could miss abdominal fat growth because two women of the same age may have the same BMI but different distribution of fat in their body, she added.

“Historically, there’s been a disproportionate emphasis on BMI and cardiovascular disease,” said El Khoudary. “Through this long-running study, we’ve found a clear link between growth in abdominal fat and risk of cardiovascular disease that can be tracked with a measuring tape but could be missed by calculating BMI. If you can identify women at risk, you can help them modify their lifestyle and diet early to hopefully lower that risk.”

Late last year, El Khoudary led a team in publishing a new scientific statement for the American Heart Association that calls for increased awareness of the cardiovascular and metabolic changes unique to the menopausal transition and the importance of counseling women on early interventions to reduce cardiovascular disease risk factors.

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Lonely adolescents are susceptible to internet addiction: Increasing numbers at risk in the coronavirus situation

teen internet

Loneliness is a risk factor associated with adolescents being drawn into compulsive internet use. The risk of compulsive use has grown in the coronavirus pandemic: loneliness has become increasingly prevalent among adolescents, who spend longer and longer periods of time online.

A study investigating detrimental internet use by adolescents involved a total of 1,750 Finnish study subjects, who were studied at three points in time: at 16, 17 and 18 years of age. The results have been published in the Child Development journal.

Adolescents’ net use is a two-edged sword: while the consequences of moderate use are positive, the effects of compulsive use can be detrimental. Compulsive use denotes, among other things, gaming addiction or the constant monitoring of likes on social media and comparisons to others.

“In the coronavirus period, loneliness has increased markedly among adolescents. They look for a sense of belonging from the internet. Lonely adolescents head to the internet and are at risk of becoming addicted. Internet addiction can further aggravate their malaise, such as depression,” says Professor of Education and study lead Katariina Salmela-Aro from the University of Helsinki.

Highest risk for 16-year-old boys

The risk of being drawn into problematic internet use was at its highest among 16-year-old adolescents, with the phenomenon being more common among boys.

For some, the problem persists into adulthood, but for others it eases up as they grow older. The reduction of problematic internet use is often associated with adolescent development where their self-regulation and control improve, their brains adapt and assignments related to education direct their attention.

“It’s comforting to know that problematic internet use is adaptive and often changes in late adolescence and during the transition to adulthood. Consequently, attention should be paid to the matter both in school and at home. Addressing loneliness too serves as a significant channel for preventing excessive internet use,” Salmela-Aro notes.

It was found in the study that the household climate and parenting also matter: the children of distant parents have a higher risk of drifting into detrimental internet use. If parents are not very interested in the lives of their adolescents, the latter may have difficulty drawing the lines for their actions.

Problematic net use and depression form a cycle

In the study participants, compulsive internet use had a link to depression. Depression predicted problematic internet use, while problematic use further increased depressive symptoms.

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Identifying risk factors for elevated anxiety in young adults during COVID-19 pandemic

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A new study has identified early risk factors that predicted heightened anxiety in young adults during the coronavirus (COVID-19) pandemic. The findings from the study, supported by the National Institutes of Health and published in the Journal of the American Academy of Child and Adolescent Psychiatry, could help predict who is at greatest risk of developing anxiety during stressful life events in early adulthood and inform prevention and intervention efforts.

The investigators examined data from 291 participants who had been followed from toddlerhood to young adulthood as part of a larger study on temperament and socioemotional development. The researchers found that participants who continued to show a temperament characteristic called behavioral inhibition in childhood were more likely to experience worry dysregulation in adolescence (age 15), which in turn predicted elevated anxiety during the early months of the COVID-19 pandemic when the participants were in young adulthood (around age 18).

“People differ greatly in how they handle stress,” said Daniel Pine, M.D., a study author and chief of the National Institute of Mental Health (NIMH) Section on Development and Affective Neuroscience. “This study shows that children’s level of fearfulness predicts how much stress they experience later in life when they confront difficult circumstances, such as the pandemic.”

Behavioral inhibition is a childhood temperament characterized by high levels of cautious, fearful, and avoidant responses to unfamiliar people, objects, and situations. Previous studies have established that children who display behavioral inhibition are at increased risk of developing anxiety disorders later. However, less research has investigated the specific mechanisms by which a stable pattern of behavioral inhibition in childhood is linked to anxiety in young adulthood.

The authors of this study hypothesized that children who demonstrate a stable pattern of behavioral inhibition may be at greater risk for worry dysregulation in adolescence—that is, difficulties managing worry and displaying inappropriate expressions of worry—and this would put them at greater risk for later heightened anxiety during stressful events like the pandemic.

In the larger study, behavioral inhibition was measured at ages 2 and 3 using observations of children’s responses to novel toys and interaction with unfamiliar adults. When the children were 7 years old, they were observed for social wariness during an unstructured free play task with an unfamiliar peer. Worry dysregulation was assessed at age 15 through a self-report survey. For the current study, the participants, at an average age of 18, were assessed for anxiety twice during the early months of the COVID-19 pandemic after stay-at-home orders had been issued (first between April 20 and May 15 and approximately a month later).

At the first assessment, 20% of the participants reported moderate levels of anxiety symptoms considered to be in the clinical range. At the second assessment, 18.3% of participants reported clinical levels of anxiety. As expected, the researchers found that individuals with high behavioral inhibition in toddlerhood who continued to display high levels of social wariness in childhood reported experiencing dysregulated worry in adolescence, and this ultimately predicted increased anxiety in young adulthood during a critical stage of the pandemic. This developmental pathway was not significant for children who showed behavioral inhibition in toddlerhood but displayed low levels of social wariness later in childhood.

“This study provides further evidence of the continuing impact of early life temperament on the mental health of individuals,” said Nathan A. Fox, Ph.D., Distinguished University Professor and director of the Child Development Lab at the University of Maryland, College Park, and an author of the study. “Young children with stable behavioral inhibition are at heightened risk for increased worry and anxiety, and the context of the pandemic only heightened these effects.”

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This is why the risk of carbon monoxide poisoning increases in winter

Carbon monoxide chat isn’t the most thrilling – but it can save lives.

According to research from Uswitch.com, fire services are being called to 10% more carbon monoxide incidents in homes than they were five years ago.

But perhaps the scariest part is that almost a third (32%) of households say they do not have an alarm to detect the deadly gas in the first palace. 

What’s more, a drop in temperatures – like the cold snap we are having now – can increase the chances of carbon monoxide poisoning.

This is because carbon monoxide can leak from malfunctioning heating appliances, commonly brought out when it gets really chilly.

‘With temperatures dropping and cold weather settling in, people naturally turn on their gas heating, light their fireplaces or start-up portable heating devices.

‘Often, they do so without having checked that these devices have been tested for carbon monoxide leaks, which is produced when fuels such as gas, oil, coal, and wood do not burn fully,’ says Andrew Hobbs, CEO of Better Indoors – an air quality testing provider.

He tells Metro.co.uk: ‘Some households in financial vulnerability or living in poor quality housing may resort to using their gas cookers for warmth, because a heater breaks and they cannot afford to replace it, leaving them especially susceptible to poisoning.’

Because you can’t see or smell carbon monoxide, you’ll probably be unaware of a leak – making it highly dangerous.

Andrew says there are around 60 deaths every year from accidental carbon monoxide poisoning in England and Wales.

How can people protect against carbon monoxide leaks?

Andrew adds: ‘We take on average 30,000 breaths each day and spend 80-90% of our time indoors. Because we cannot see what is in the air we are breathing, we assume it is clean and safe.’

The difficult thing about carbon monoxide is that, without an alarm, you won’t even notice it.

‘It’s therefore critical that you install carbon monoxide alarms on every floor of your home,’ he adds. 

What are the signs of carbon monoxide poisoning?

The most common symptoms of CM poisoning are headache, dizziness, weakness, upset stomach, vomiting, chest pain and confusion.

But the tricky thing is that the symptoms are very similar to flu, colds and Covid, so you might not immediately realise it’s to do with a carbon monoxide leak.

If you suspect a problem, immediately open all doors and windows and go outside for fresh air. Then call the National Gas Emergency Service on 0800 111 999.

What happens when you breathe in carbon monoxide?

Sara Quayle, who specialises in helping companies and individuals with safety and first aid at work and home, explains what happens when we breathe in the dangerous gas.

She tells Metro.co.uk: ‘When you breathe in carbon monoxide it enters your bloodstream and mixes with your haemoglobin the part of the red blood cells that carry oxygen around your body. Therefore your blood can no longer get oxygen around your body and this then causes the bodies cells and tissues to fail and die.

‘It is so important to have early recognition of carbon monoxide poisoning as you can recover from it but the longer you are in an atmosphere with carbon monoxide the more serious the outcome.

‘This can lead to long-term health issues or death.’

What regular checks should people be doing?

Andrew says: ‘Every year make sure you ask a Gas Safe Registered engineer to check that any gas equipment in your home is installed correctly and tested. 

‘This will include heaters, cookers, fires as well as your boilers and any water heaters. Chimneys and flues should also be regularly cleaned to prevent blockages.’

It’s also vital to have carbon monoxide alarms installed within your home and that batteries are checked frequently.

These alarms usually cost around £15 – a small price to pay for potentially saving your life.

Are certain houses more susceptible to it?

It’s worth pointing out that anyone living in a flat should be mindful of other potential carbon monoxide sources from people living in your building. 

Andrew says: ‘Often carbon monoxide levels can enter your home from theirs via the ventilation system.

‘Also because flats are typically smaller than houses, you should take extra care to keep your own space well-ventilated, and be especially wary when utilising indoor heaters, as they have the potential to release high levels of CM that could rapidly accumulate in an enclosed area.’

The best thing to do is to speak to your landlord and make sure they have installed carbon monoxide detectors in shared spaces and in any rooms used as living accommodation where solid fuel is used. 

Any landlords that fail to comply with the regulations could face a fine.

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Immune response to insulin could identify, help treat those at risk for type 1 diabetes

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Researchers from the Barbara Davis Center for Childhood Diabetes at the University of Colorado Anschutz Medical Campus have found that immune responses to insulin could help identify individuals most at risk for developing Type 1 diabetes.

The study, out recently in the Proceedings of the National Academy of Sciences, measured immune responses from individuals genetically predisposed to developing Type 1 diabetes (T1D) to naturally occurring insulin and hybrid insulin peptides. Since not all genetically predisposed individuals develop T1D, researchers sought to examine T-cell immune responses from the peripheral blood that could occur before the onset of clinical diabetes.

“We want to know why people develop T1D, and this research has helped provide a lot more information and data as to what it looks like when genetically at-risk individuals are headed towards clinical diagnosis,” says Aaron Michels, MD, the study’s lead researcher, Associate Professor of Medicine at CU Anschutz and researcher at the Barbara Davis Center. “Ideally, you want to treat a disease when it’s active, so this is a need in our field to understand when people have an immune response directed against insulin producing cells.”

Researchers collected blood samples from genetically at-risk adolescents every 6 months for two years. Inflammatory T-cell responses to hybrid insulin peptides correlated with worsening blood glucose measurements and progression to T1D development. The results indicate an important advancement in identifying the risk of T1D early as well as the potential for intervention.

“There are now therapies used in research studies that have delayed the onset of clinical type 1 diabetes,” says Michels. “Patients with these specific immune responses, may benefit from immune intervention to delay T1D onset and possibly prevent it for years.”

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Researchers launch Spermine Risk Score for prostate cancer diagnosis

HKBU and CUHK launch Spermine Risk Score for prostate cancer diagnosis

Researchers from Hong Kong Baptist University (HKBU) and the Faculty of Medicine at The Chinese University of Hong Kong (CU Medicine) have jointly developed the Spermine Risk Score which, coupled with the use of a urine test, provides a non-invasive and more reliable method for the diagnosis of prostate cancer. In a study conducted by the researchers, about 37% of the patients, who were ultimately found to have no prostate cancer, can avoid undergoing a prostate biopsy procedure. The findings have just been published in the scientific journal Prostate Cancer and Prostatic Diseases.

Demand for more reliable and non-invasive diagnosis

Prostate cancer is the third most common and the fourth most fatal cancer for the male population in Hong Kong. It results from the abnormal and uncontrolled growth of the prostate gland. Two medical procedures are commonly used for its diagnosis, namely the digital rectal examination (DRE) and the serum prostate-specific antigen (PSA) test.

DRE is performed by a doctor who uses a gloved finger to check the back portion of the prostate. Its accuracy highly depends on the skill and experience of the doctor. The PSA test, a kind of blood test, is a more popular alternative. For the Asian population, individuals with a PSA level higher than 4 ng/mL are normally interpreted as having a high risk of prostate cancer, and a prostate biopsy for further confirmation is usually recommended. According to the Centre for Health Protection of the Department of Health, about three out of four men in this group do not have prostate cancer. However, the patients have to bear the risk of complications due to the invasive nature of the prostate biopsy procedure.

Prostate cancer patients have lower spermine levels

In search of a more reliable and non-invasive method for prostate cancer diagnosis, Professor Gary Wong Ka-leung, Professor and Head of the Department of Chemistry at HKBU, and Professor Ng Chi-fai and Dr. Peter Chiu Ka-fung, Professor and Associate Professor respectively of the Division of Urology in the Department of Surgery at CU Medicine, have collaborated since 2014 to identify a new biomarker to supplement the PSA test. They found that prostate cancer patients in general have lower levels of spermine, a biogenic molecule in their urine, which offers a clue for the diagnosis of prostate cancer.

To investigate the diagnostic performance of spermine, the research team recruited 905 patients between 2015 and 2019 to participate in a study. All of them had elevated PSA levels and/or abnormal DRE, with a prostate biopsy scheduled.

Score to estimate prostate cancer risk

Among the 905 patients, 600 of them who had PSA levels ranging from 4 to 20 ng/mL were included in the analysis. Their urine samples were collected before they underwent a biopsy procedure. The biopsy results showed that out of the 600 patients, 185 (30.8%) were diagnosed with prostate cancer.

At the same time, the urine samples of these 600 patients were also analyzed. The results found that about 49% of the patients with spermine levels in the lowest quartile had prostate cancer, which was nearly triple the number of patients in the highest quartile (17%). The research team then used the urine spermine level figures and three other clinical parameters, namely DRE, PSA level and prostate volume, to develop the Spermine Risk Score, with the objective of offering a more accurate estimation of patients’ prostate cancer risk.

The higher the Spermine Risk Score, the greater the patient’s risk of developing prostate cancer. Only patients with Spermine Risk Scores higher than 6.2 will be advised to undergo the biopsy procedure. Based on Spermine Risk Scores calculated with data collected from the study, about 37% of the non-cancer patients could have avoided the biopsy procedure. Moreover, the negative predictive value of the Spermine Risk Score for significant prostate cancer is 95%, which means the chance of no significant cancer is 95% if the value of the Score is negative.

Promising approach for prostate cancer diagnosis

Dr. Chiu concluded the findings by highlighting that, “This study confirms that urine spermine and the Spermine Risk Score are effective at identifying men at higher risk of prostate cancer and the test could help reduce the number of unnecessary biopsies.”

“It is the first prospective study to investigate the efficacy of urine spermine in prostate cancer detection. It successfully demonstrated that the Spermine Risk Score, developed based on patients’ urine spermine levels and other clinical parameters, can serve as a novel and promising approach to address the limitations of the diagnostic methods currently in use,” said Professor Wong.

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Parkinson’s disease risk and severity is tied to a channel in cells’ ‘recycling centers

Parkinson's disease

Many genetic mutations have been found to be associated with a person’s risk of developing Parkinson’s disease. Yet for most of these variants, the mechanism through which they act remains unclear.

Now a new study in Nature led by a team from the University of Pennsylvania has revealed how two different variations—one that increases disease risk and leads to more severe disease in people who develop Parkinson’s and another that reduces risk—manifest in the body.

The work, led by Dejian Ren, a professor in the School of Arts & Sciences’ Department of Biology, showed that the variation that raises disease risk, which about 17% of people possess, causes a reduction in function of an ion channel in cellular organelles called lysosomes, also known as cells’ waste removal and recycling centers. Meanwhile, a different variation that reduces Parkinson’s disease risk by about 20% and is present in 7% of the general population enhances the activity of the same ion channel.

“We started with the basic biology, wanting to understand how these lysosomal channels are controlled,” says Ren. “But here we found this clear connection with Parkinson’s disease. To see that you can have a variation in an ion channel gene that can change the odds of developing Parkinson’s both ways—increasing and decreasing it—is highly novel.”

The fact that the channel seems to play a crucial role in Parkinson’s also makes it an appealing potential target for a drug that could slow the disease’s progression, the researchers note.

Scientists have understood since the 1930s that cells use carefully regulated ion channels embedded in their plasma membrane to control crucial aspects of their physiology, such as shuttling electrical impulses between neurons and from neurons to muscles.

But it wasn’t until the past decade that researchers began to appreciate that the organelles within cells that have membranes, including endosomes and lysosome, also relied on ion channels to communicate.

“One reason is it’s hard to look at them because organelles are really small,” Ren says. During the last several years, his lab overcame this technical challenge and began studying these membrane channels and measuring the current of ions that crosses through them.

These ions pass through channel proteins that open and close in response to specific factors. About five years ago, Ren’s group identified one membrane protein, TMEM175, that forms a channel allowing potassium ions to move in and out.

Around the same time, other teams doing genome-wide association studies found two variations in TMEM175 that influenced Parkinson’s disease risk, turning it up or down.

“One variation is associated with a 20-25% increase in the odds of getting Parkinson’s in the general population,” Ren says. “And if you look only at people who have been diagnosed with Parkinson’s, the frequency of that variation is even higher.”

Intrigued by the connection, Ren reached out to Penn physician-scientist Alice Chen-Plotkin, who works with patients who have Parkinson’s, to collaborate. In data from Parkinson’s disease patients, she and colleagues found that motor and cognitive impairments progressed more rapidly in those patients who carried one of the TMEM175 genetic variations Ren was studying.

To find out what this variation was actually doing in cells, Ren’s lab turned a close eye to lysosomes. In isolation, they found that the potassium current through TMEM175 was activated by growth factors, proteins like insulin that respond to the presence of nutrients in the body. And they confirmed that TMEM175 appeared to be the only active potassium channel in mouse lysosomes.

“When you starve a cell, this protein is not functional anymore,” Ren says. “That was exciting to us because that tells us this is a major mechanism that can be used by the organelle to receive communications from the outside of the cell and maybe send communication back out.”

They found that a kinase enzyme called AKT, which is typically thought to achieve its ends by adding a small molecule called a phosphate group to whatever protein it is acting upon, joined with TMEM175 to open the protein channel. But AKT opened it without introducing a phosphate group. “The textbook definitation of a kinase is that it phosphorylates proteins,” Ren says. “To find this kinase acting without doing that was very surprising.”

They next turned to mice genetically engineered to carry the same variations that had been found in the human population to see how the genetic changes affected the animals’ ion channel activity. Mice with the disease-risk-increasing mutation had a potassium current of just about 50% of that of normal mice, and that current was extinguished in the absence of growth factors. In contrast, the ion channels in mice with the disease-risk-reducing mutation continued operating for several hours in the absence of growth factors, even longer than they did in normal mice.

“This tells you this mutation is somehow helping the mice resist the effects of nutrient depletion,” Ren says.

To measure effects on neurons, they observed that the neurons with the mutation in cell culture associated with more severe Parkinson’s were more susceptible to damage from toxins and nutrient depletion. “If the same is true in human neurons, that means 17% of the population carries a variation that may make their neurons more damaged when subjected to stressors,” says Ren.

Collaborating with Penn researcher Kelvin Luk, the investigators looked at levels of misfolded protein in neurons in cell culture. Known in humans as Lewy bodies and a defining characteristic of Parkinson’s, these inclusions increased “strikingly” within neurons when TMEM175 function declined, Ren says. This is likely due to an impairment in the function of lysosomes, which normally help digeset and recycle waste generated by the cell.

And, also associated with human Parkinson’s, mice lacking TMEM175 lost a portion of the neurons that produce the neurotransmitter dopamine and performed worse on tests of coordination than normal mice.

Together with the findings in humans, the researchers believe their work points to a significant contributor to the pathology of Parkinson’s disease. Moving forward, Ren’s group hopes to delve deeper into the mechanism through which this ion channel is regulated. Their research may shed light not only on the molecular impairments involved in Parkinson’s but also in other neurodegenerative diseases, particular those related to lysosomes, which include a number of rare but very severe conditions.

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Coronavirus new strain: Dr Hilary shares ‘major’ risk factor you can change for COVID-19

Coronavirus: New strain 'significantly more risky' says expert

CORONAVIRUS is an indiscriminate threat – it can seriously affect anyone of any age. However, researchers have found a strong association between one’s health and the risk of severe COVID-19. Speaking on GMB on Tuesday, Dr Hilary issued a dire warning about excess weight. He said: “Obesity causes general inflammation in the body and that’s a major risk factor for COVID-19.”

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Study finds genetic clues to pneumonia risk and COVID-19 disparities

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Researchers at Vanderbilt University Medical Center and colleagues have identified genetic factors that increase the risk for developing pneumonia and its severe, life-threatening consequences.

Their findings, published recently in the American Journal of Human Genetics, may aid efforts to identify patients with COVID-19 at greatest risk for pneumonia, and enable earlier interventions to prevent severe illness and death.

Despite the increasing availability of COVID-19 vaccines, it will take months to inoculate enough people to bring the pandemic under control, experts predict. In the meantime, thousands of Americans are hospitalized and die from COVID-19 each day.

“This study is so important because we performed analyses separately in participants of Caucasian ancestry as well as African ancestry to identify genetic risk factors contributing to pneumonia susceptibility and severity,” said Jennifer “Piper” Below, Ph.D., associate professor of Medicine and the paper’s corresponding author.

“Combined with systemic racism and socioeconomic factors that have been reported by others, these genetic risk differences may contribute to some of the disparities we observe in COVID-19 outcomes,” Below said.

The researchers conducted genome-wide association studies (GWAS) of more than 85,000 patients whose genetic information is stored in VUMC’s BioVU biobank and which has been linked to “de-identified” electronic health records stripped of personal identifying information. GWAS can identify associations between genetic variations and disease.

With colleagues from the University of North Carolina at Chapel Hill, the University of Texas MD Anderson Cancer Center in Houston, and the Icahn School of Medicine at Mount Sinai in New York, the VUMC researchers identified nearly 9,000 cases of pneumonia in patients of European ancestry, and 1,710 cases in patients of African ancestry.

The strongest pneumonia association in patients of European ancestry was the gene that causes cystic fibrosis (CF). This disease produces abnormally thick mucus leading to chronic infections and progressive respiratory failure.

In patients of African ancestry, the strongest pneumonia association was the mutation that causes sickle cell disease (SCD), a red blood cell disorder that increases the risk for pneumonia, influenza and acute respiratory infections.

Children with CF and SCD are at particular risk for severe disease if they contract COVID-19.

The researchers found that “carriers” who are unaffected by CF yet carry a copy of the CF gene had a heightened susceptibility to pneumonia, and those who are unaffected by SCD yet carry a copy of the SCD mutation were at increased risk for severe pneumonia.

Further studies will be needed to determine whether these carriers also bear “a silent, heightened risk for poor outcomes from COVID-19,” the researchers said.

To identify other genetic variations that increase pneumonia risk, they removed patients with CF and SCD from their analysis, repeated the GWAS, and used another technique called PrediXcan, which correlates gene expression data with traits and diseases in the electronic health record.

This time they found a pneumonia-associated variation in a gene called R3HCC1L in patients of European ancestry, and one near a gene called UQCRFS1 in patients of African ancestry. The molecular function of R3HCC1L is unclear, but deletion of the UQCRFS1 in mice disrupts part of their infection-fighting immune response.

“Although our understanding about the genetic mechanism of pneumonia is still limited, this study identified the novel candidate genes, R3HCC1L and UQCRFS1, and offered an insight for further host genetic studies of COVID-19,” said the paper’s first author, Hung-Hsin Chen, Ph.D., MS, a postdoctoral fellow in Below’s lab.

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Metformin use reduces risk of death for patients with COVID-19 and diabetes

metformin

Use of the diabetes drug metformin—before a diagnosis of COVID-19—is associated with a threefold decrease in mortality in COVID-19 patients with Type 2 diabetes, according to a racially diverse study at the University of Alabama at Birmingham. Diabetes is a significant comorbidity for COVID-19.

“This beneficial effect remained, even after correcting for age, sex, race, obesity, and hypertension or chronic kidney disease and heart failure,” said Anath Shalev, M.D., director of UAB’s Comprehensive Diabetes Center and leader of the study.

“Since similar results have now been obtained in different populations from around the world—including China, France and a UnitedHealthcare analysis—this suggests that the observed reduction in mortality risk associated with metformin use in subjects with Type 2 diabetes and COVID-19 might be generalizable,” Shalev said.

How metformin improves prognosis in the context of COVID-19 is not known, Shalev says. The UAB findings suggest that the mechanisms may go beyond any expected improvement in glycemic control or obesity, since neither body mass index, blood glucose nor hemoglobin A1C were lower in the metformin users who survived as compared to those who died.

“The mechanisms may involve metformin’s previously described anti-inflammatory and anti-thrombotic effects,” Shalev said.

The study—first made available in MedRxiv and now published in the peer-reviewed journal Frontiers in Endocrinology—included 25,326 patients tested for COVID-19 at the tertiary care UAB Hospital between Feb. 25 and June 22 of last year. Of the 604 patients found to be COVID-19-positive, 311 were African Americans.

The primary outcome in the study was mortality in COVID-19-positive subjects, and the potential association with subject characteristics or comorbidities was analyzed.

Researchers found that Blacks, who are only 26 percent of Alabama’s population, were 52 percent of those who tested positive for COVID-19, and only 30 percent of those who tested negative. In contrast, only 36 percent of the COVID-19-positive subjects were white, while whites made up 56 percent of those who tested negative, further underlining the racial disparity. Once COVID-19-positive though, no significant racial difference in mortality was observed.

“In our cohort,” Shalev said, “being African American appeared to be primarily a risk factor for contracting COVID-19, rather than for mortality. This suggests that any racial disparity observed is likely due to exposure risk and external socioeconomic factors, including access to proper health care.”

Overall mortality for COVID-19-positive patients was 11 percent. The study found that 93 percent of deaths occurred in subjects over the age of 50, and being male or having high blood pressure was associated with a significantly elevated risk of death. Diabetes was associated with a dramatic increase in mortality, with an odds ratio of 3.62. Overall, 67 percent of deaths in the study occurred in subjects with diabetes.

The researchers looked at the effects of diabetes treatment on adverse COVID-19 outcomes, focusing on insulin and metformin as the two most common medications for Type 2 diabetes. They found that prior insulin use did not affect mortality risk.

However, prior metformin use was a different matter. Metformin use significantly reduced the odds of dying, and the 11 percent mortality for metformin users was not only comparable to that of the general COVID-19-positive population, it was dramatically lower than the 23 percent mortality for diabetes patients not on metformin.

After controlling for other covariates, age, sex and metformin use emerged as independent factors affecting COVID-19-related mortality. Interestingly, even after controlling for all these other covariates, death was significantly less likely—with an odds ratio of 0.33—for Type 2 diabetes subjects taking metformin, compared with those who did not take metformin.

“These results suggest that, while diabetes is an independent risk factor for COVID-19-related mortality,” Shalev said, “this risk is dramatically reduced in subjects taking metformin—raising the possibility that metformin may provide a protective approach in this high-risk population.”

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