Tag: 9/5/24

Categories : GeneticsTags :

Genomic ‘Butterfly Effect’ Explains Risk for Autism spectrum Disorder

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Photo by Sangharsh Lohakare on Unsplash

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.

Source: RIKEN

Categories : Skeletal SystemTags :

Poor Sleep When Young may Drive Osteoporosis in Later Life

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Photo by Andrea Piacquadio

Adequate sleep can help prevent osteoporosis, according to a growing body of research. As part of the University of Colorado Department of Medicine’s annual Research Day, held on April 23, faculty member Christine Swanson, MD, MCR, described her clinical research on how sleep interacts with osteoporosis.

“Osteoporosis can occur for many reasons such as hormonal changes, aging, and lifestyle factors,” said Swanson, an associate professor in the Division of Endocrinology, Metabolism, and Diabetes. “But some patients I see don’t have an explanation for their osteoporosis.

“Therefore, it’s important to look for novel risk factors and consider what else changes across the lifespan like bone does – sleep is one of those,” she added.

How bone density and sleep change over time

In people’s early- to mid-20s, they reach what is called peak bone mineral density, which is higher for men than it is for women, Swanson said. This peak is one of the main determinants of fracture risk later in life.

Bone density mostly plateaus for a couple of decades. Then, when women enter the menopausal transition, they experience accelerated bone loss. Men also experience bone density decline as they age.

Sleep patterns also evolve over time. As people get older, their total sleep time decreases, and their sleep composition changes. For instance, sleep latency, which is the time it takes to fall asleep, increases with age. On the other hand, slow wave sleep, which is deep restorative sleep, decreases as we age.

“And it’s not just sleep duration and composition that change. Circadian phase preference also changes across the lifespan in both men and women,” Swanson said, referring to people’s preference for when they go to sleep and when they wake up.

How is sleep linked to bone health?

Genes that control our internal clock are present in all of our bone cells, Swanson said.

“When these cells resorb and form bone, they release certain substances into the blood that let us estimate how much bone turnover is going on at a given time,” she said.

These markers of bone resorption and formation follow a daily rhythm. The amplitude of this rhythm is larger for markers of bone resorption than it is for markers of bone formation, she said.

“This rhythmicity is likely important for normal bone metabolism and suggests that sleep and circadian disturbance could directly affect bone health,” she said.

Researching the connection between sleep and bone health

To further understand this relationship, Swanson and colleagues researched how markers of bone turnover responded to cumulative sleep restriction and circadian disruption.

For this study, participants lived in a completely controlled inpatient environment. The participants did not know what time it was, and they were put on a 28-hour schedule instead of a 24-hour day.

“This circadian disruption is designed to simulate the stresses endured during rotating night shift work and is roughly equivalent to flying four time zones west every day for three weeks,” she said. “The protocol also caused participants to get less sleep.”

The research team measured bone turnover markers at the beginning and end of this intervention and found significant detrimental changes in bone turnover in both men and women in response to the sleep and circadian disruption. The detrimental changes included declines in markers of bone formation that were significantly greater in younger individuals in both sexes compared to the older individuals.

In addition, young women showed significant increases in the bone resorption marker.

If a person is forming less bone while still resorbing the same amount – or even more – then, over time, that could lead to bone loss, osteoporosis, and increased fracture risk, Swanson said.

“And sex and age may play an important role, with younger women potentially being the most susceptible to the detrimental impact of poor sleep on bone health,” she said.

Research in this area is ongoing, she added.

Source: University of Colorado Anschutz Medical Campus

Categories : Medical Research & TechnologyTags :

Can We Make Medicine Taste Less Bitter?

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Adhering to medications may no longer be a “bitter pill to swallow”

Photo by Danilo Alvesd on Unsplash

The bitter taste of certain drugs is a barrier to taking some medications as prescribed, especially for people who are particularly sensitive to bitter taste. Published in Clinical Therapeutics, a team from the Monell Chemical Senses Center found that the diabetes drug rosiglitazone could partially block the bitter taste of some especially bad-tasting medications.

“To our knowledge, there are no previous reports on the bitter-blocking effect of this diabetes drug,” said first author Ha Nguyen, PhD, Monell Postdoctoral Fellow. Rosiglitizone was identified as a potential bitter blocker using tests of human cells from taste tissue.

The team conducted taste-testing experiments on research participants in the United States and Poland, and they found that adding rosiglitazone to the medicines reduced bitterness for many, but not all, research participants.

“People differ, and we need to test many types of people from different parts of the world to make sure that efforts to reduce bitterness and make medicines easier to take work well for all people,” said senior author Danielle Reed, PhD, Monell Chief Science Officer.

These results suggest having more blockers to choose from will help entirely suppress the bitterness of many types of medicines for a wide range of populations and ancestries. Mixtures of several blockers may help attain a low-to-zero-bitterness standard for even the most bitter-tasting medicines.

“Although rosiglitazone was only partially effective as a bitter blocker in this study, modifying these drugs to improve potency, palatability, and efficacy may allow us to find a better version of this drug,” said Nguyen.

“Rosiglitazone is valuable as a bitter blocker because it is potentially effective in most people and is part of a class of drugs already approved worldwide for treating diabetes.”

Next steps in this line of research include a similar study that measures bitter blocking in several hundred African and Asian immigrants to add to the diversity of participants’ ancestries with regard to bitter taste.

Source: Monell Chemical Senses Center

Categories : Cardiovascular DiseaseTags :

Exercise, New Drug Class Recommended for Management of Hypertrophic Cardiomyopathy

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Human heart. Credit: Scientific Animations CC4.0

The American College of Cardiology (ACC) and the American Heart Association (AHA) today released a new clinical guideline for effectively managing individuals diagnosed with hypertrophic cardiomyopathy (HCM). The guideline, published in Circulation, reiterates the importance of collaborative decision-making with patients who have HCM and provides updated recommendations for the most effective treatment pathways for adult and paediatric patients.

HCM is an inherited cardiac condition most often caused by a gene mutation that makes the heart muscle too thick (hypertrophy), which impairs its ability to adequately pump blood throughout the body. HCM affects approximately 1 in every 500 individuals; however, a significant portion of cases remain undiagnosed because many people do not exhibit symptoms. Occasionally, the first time HCM is diagnosed is after a sudden death. People who do have symptoms may experience episodes of fainting, chest pain, shortness of breath or irregular heartbeats.

“Incorporating the most recent data, this new guideline equips clinicians with the latest recommendations for the treatment of HCM,” said Steve R. Ommen, MD, FACC, medical director of the Mayo Hypertrophic Cardiomyopathy Clinic and chair of the guideline writing committee. “We’re seeing more evidence that patients with HCM can return to their normal daily lives with proper care and management.”

Updated recommendations in the guideline reflect recent evidence about HCM treatment and management including new forms of pharmacologic management; participation in vigorous recreational activities and competitive sports; and risk stratification for sudden cardiac death (SCD) with an emphasis on pediatric patients.

The guideline includes recommendations for adding cardiac myosin inhibitors, a new class of medication for patients with symptomatic obstructive HCM who do not get adequate symptom relief from first-line drug therapy. Symptomatic obstructive HCM is a type of HCM where the heart muscle is restricted. Cardiac myosin inhibitors are the first FDA-approved class of medication to specifically target the thickening of the heart muscle instead of treating the symptoms, however they are monitored under the FDA’s Risk Evaluation and Mitigation Strategies (REMS) program, which may create additional steps and time for both the clinician and the patient. Clinicians require special training to prescribe the medication, and patients require regular screenings.

“These new drugs offer an alternative for patients who have failed first-line therapy and either want to delay or possibly avoid more aggressive options,” Ommen said. “With this guideline, we’re providing clinicians with point-of-care guidance about effectively using this first-in-class, evidence-based treatment option and improving their patients’ quality of life.”

In addition to medication treatment, growing evidence is showing that the benefits of exercise outweigh the potential risks for patients with HCM. Low to moderate intensity recreational exercise should be part of how HCM patients manage their overall health. For some HCM patients, competitive sports may be considered in consultation with HCM clinical specialists.

“Recommendations for physical activity continue to evolve with research,” Ommen said. “As part of a healthy lifestyle, patients with HCM are now encouraged to engage in low-to-moderate intensity physical activities. We’re seeing how vigorous physical activities can be reasonable for some individuals. With shared decision-making between the clinician and the patient, some patients may even be able to return to competitive sports.”

Poorly managed HCM may lead to many complications including SCD. The new guideline includes recommendations for assessing and managing the risk of SCD by establishing clear risk markers. Guidance for integrating risk markers with tools to estimate an individual patient’s SCD risk score is recommended to aid in the patient/clinician shared decision-making regarding implantable cardioverter defibrillator placement, incorporating a patient’s personal level of risk tolerance and specific treatment goals including quality of life.

Several recommendations in the new guideline extend to paediatric patients. A specific paediatric risk stratification for SCD is emphasised, with risk calculators specific to children and adolescents and stressing the importance of HCM centres with expertise in paediatrics. The new guideline extends exercise stress testing recommendations to include children diagnosed with HCM to help determine functional capacity and provide prognostic feedback.

Source: American College of Cardiology

Categories : Metabolic DisordersTags :

Neuropathy is More Common and is Underdiagnosed

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Source: Pixabay CC0

Neuropathy, the nerve damage that causes pain and numbness in the feet and hands and can eventually lead to falls, infection and even amputation, is very common and underdiagnosed, according to a study published in Neurology®, the medical journal of the American Academy of Neurology.

“More than one-third of people with neuropathy experience sharp, prickling or shock-like pain, which increases their rates of depression and decreases quality of life,” said study author Melissa A. Elafros, MD, PhD, of the University of Michigan in Ann Arbor and a member of the American Academy of Neurology. “People with neuropathy also have an increased risk of earlier death, even when you take into account other conditions they have, so identifying and treating people with or at risk for neuropathy is essential.”

The study involved 169 people from an outpatient internal medicine clinic serving mainly Medicaid patients in Flint, Michigan. The participants had an average age of 58 years and 69% were Black people. One-half of the people had diabetes, which can cause neuropathy. A total of 67% had metabolic syndrome, which is defined as having excess belly fat plus two or more of the following risk factors: hypertension, elevated triglycerides, hyperglycaemia and low high-density lipoprotein (HDL) cholesterol. These risk factors are also associated with neuropathy.

All participants were tested for distal symmetric polyneuropathy. Information about other health conditions was also collected. A total of 73% of the people had neuropathy. Of those, 75% had not been previously diagnosed with the condition. Nearly 60% of those with neuropathy were experiencing pain. Of those with neuropathy, 74% had metabolic syndrome, compared to 54% of those who did not have neuropathy.

After adjusting for other factors that could affect the risk of neuropathy, researchers found that people with metabolic syndrome were more than four times more likely to have neuropathy than people who did not have the syndrome.

Risk differs according to race

Researchers were also looking for any relationship between race and income and neuropathy, as few studies have been done on those topics. There was no relationship between low income and neuropathy. For race, Black people had a decreased risk of neuropathy. Black people made up 60% of those with neuropathy and 91% of those without neuropathy.

“The amount of people with neuropathy in this study, particularly undiagnosed neuropathy, was extraordinarily high with almost three fourths of the study population,” Elafros said. “This highlights the urgent need for interventions that improve diagnosis and management of this condition, as well as the need for managing risk factors that can lead to this condition.” A limitation of the study is that it is a snapshot in time; it did not follow people to see who developed neuropathy over time. It also did not look at reasons why people were not able to manage risk factors that can lead to neuropathy.

Source: American Academy of Neurology