Tag: 7/7/23

Categories : Diet and Nutrition GeneticsTags :

Obesity Genetic Risk Could be Curbed by Practising Restraint

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Photo by Jonathan Borba

Obesity risk genes make people feel hungrier and lose control over their eating, but practisng dietary restraint could counteract this, according to new research from University of Exeter. Published in the International Journal of Epidemiology, the study found that those with higher genetic risk of obesity can reduce the effects that are transmitted via hunger and uncontrolled eating by up to half through dietary restraint.

Lead author psychology PhD student, Shahina Begum said: “At a time when high calorie foods are aggressively marketed to us, it’s more important than ever to understand how genes influence BMI. We already know that these genes impact traits and behaviours such as hunger and emotional eating, but what makes this study different is that we tested the influence of two types of dietary restraint – rigid and flexible – on the effect of these behaviours. What we discovered for the first time was that increasing both types of restraint could potentially improve BMI in people genetically at risk; meaning that restraint-based interventions could be useful to target the problem.”

Genes linked to obesity increase BMI, with up to a quarter of this effect explained by increases in hunger and uncontrolled (including emotional) eating. There are over 900 genes that have so far been identified by researchers as being associated with BMI and several studies suggest these risk genes influence feelings of hunger and loss of control towards food.

This study examined 3780 adults aged between 22 and 92 years old from two UK cohorts: the Genetics of Appetite Study, and Avon Longitudinal Study of Parents and Children. Their weight and height were measured, and they provided a DNA sample via their blood to calculate an overall score for their genetic risk of obesity. They then completed questionnaires to measure 13 different eating behaviours, including disinhibition (a tendency to engage in binge or emotional eating) and over-eating due to hunger.

As expected, researchers found that a higher genetic risk score was associated with a higher BMI, partly due to increased disinhibition and hunger. However, results also found that those who had high levels of dietary restraint reduced those effects by almost half for disinhibition and a third for hunger, suggesting that restraint may counteract some of the effects of genetic risk.

There are different types of dietary restraint, including flexible strategies to rigid strategies, like calorie counting. The study tested the influence of both types of restraint for the first time and found both could potentially improve BMI in people genetically at risk.

Interventions to facilitate dietary restraint could include changing the food environment (by reducing the calorie content or portion size of food) or supporting individuals. To this end, members of the research team have developed a Food Trainer app (https://www.exeter.ac.uk/research/foodt/) to help achieve that. The app works as a game that trains people to repeatedly stop to high calorie food and research suggests this training may be particularly beneficial for those with a higher BMI.

Source: University of Exeter

Categories : Genetics Mental HealthTags :

Schizophrenia Might Stem From Genetic Mutations In Utero

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Photo by Alex Green on Pexels

As an adult-onset psychiatric disorder, schizophrenia is thought to be triggered by some combination of environmental factors and genetics, although the exact cause remains unclear. In a study published in the journal Cell Genomics, researchers find a correlation between schizophrenia and somatic copy-number variants, a type of mutation that occurs early in development but after genetic material is inherited. This study is one of the first to rigorously describe the relationship between somatic genetic mutations and schizophrenia risk.

“We originally thought of genetics as the study of inheritance. But now we know that genetic mechanisms go way beyond that,” says senior author Chris Walsh, an investigator at the Howard Hughes Medical Institute and chief of genetics and genomics at Boston Children’s Hospital. “We’re looking at mutations that are not inherited from the parents.”

The researchers analysed genotype-marker data from over 20,000 blood samples of people with or without schizophrenia from the Psychiatric Genomics Consortium. They ultimately identified two genes, NRXN1 and ABCB11, that correlated with schizophrenia cases when disrupted in utero. NRXN1, a gene that helps transmit signals throughout the brain, has been associated with schizophrenia before. However, this is the first study to associate somatic, not inherited, NRXN1 mutations with schizophrenia.

Unlike inherited mutations, which are present in all the cells of the body, somatic mutations are only present in a fraction of cells based on when and where a mutation occurred. If a mutation occurs early in development, it is expected that the variant is present throughout the body in a mosaic pattern. On the basis of this principle, researchers can identify somatic mutations that occurred early in development and are present not only in the brain but also in a fraction of cells in the blood.

“If a mutation occurs after fertilisation when there are only two cells, the mutation will be present in half of the cells of the body,” says Walsh. “If it occurs in one of the first four cells, it will be present in about a quarter of the cells of the body, and so on.”

The second gene the researchers identified, ABCB11, is most known to encode a liver protein. “That one came out of nowhere for us,” says Eduardo Maury, a student in Harvard-MIT’s MD-PhD program. “There have been some studies associating mutations in this gene with treatment-resistant schizophrenia, but it hasn’t been strongly implicated in schizophrenia per se.”

When the team investigated further, they found that ABCB11 is also expressed in very specific subsets of neurons that carry dopamine from the brainstem to the cerebral cortex. Most schizophrenia drugs are thought to act on these cells to decrease an individual’s dopamine levels, so this might explain why the gene is associated with treatment resistance.

Next, the team is working towards identifying other acquired mutations that might be associated with schizophrenia. Given that the study analysed blood samples, it will be important to look at more brain-specific mutations that might have been too subtle or recent in a patient’s life for this analysis to detect. In addition, somatic deletions or duplications might be an under-investigated risk factor associated with other disorders.

“With this study, we show that it is possible to find somatic variants in a psychiatric disorder that develops in adulthood,” says Maury. “This opens up questions about what other disorders might be regulated by these kinds of mutations.”

Source: Cell Press via ScienceDaily

Categories : Obstetrics & GynaecologyTags :

Foetal Exposure to THC could Lead to Long-lasting Health Impacts

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Photo by Pavel Danilyuk on Pexels

Consuming THC (Delta-9-tetrahydrocannabinol) while pregnant could potentially affect development of the foetus and lead to life-long health impacts for offspring, according to a new study published in the journal Clinical Epigenetics.

THC is the main psychoactive ingredient in cannabis, which is growing in popularity and availability. The prevalence of cannabis use in pregnancy is also rapidly increasing, especially during the first trimester, when the foetus is most vulnerable to environmental exposures, to mitigate common symptoms like morning sickness. However, the potential effects of prenatal cannabis use on foetal development remain inconclusive, in part due to a lack of safety data. This study aimed to identify the potential long-term health impacts of THC use during pregnancy.

In a non-human primate model, Oregon Health & Science University researchers found that exposing a pregnant subject to THC altered placental and foetal epigenetics. Researchers also found that that these changes to gene regulation and expression are consistent with those seen with many common neurobehavioural conditions, including autism spectrum disorder.

“Cannabis is one of the most commonly used drugs and is widely available across the country, so there is a common perception that its completely safe to use,” said the study’s lead author Lyndsey Shorey-Kendrick, PhD, a computational biologist in the Division of Neurosciences at OHSU’s Oregon National Primate Research Center, or ONPRC. “The reality is that cannabis still carries many health risks for certain populations, including those who are pregnant. If we’re able to better understand the impacts, we can more effectively communicate the risks to patients and support safer habits during the vulnerable prenatal period.”

In a model using nonhuman primates, researchers administered THC in a daily edible and compared its effects to a group receiving a placebo. Specifically, researchers evaluated the epigenetic changes in several key areas that indicate healthy prenatal development: the placenta and foetal lung, brain and heart.

When looking at these areas, analyses showed that THC exposure altered the epigenome, meaning a process in which the information encoded in a gene is turned into a function or observable trait. Genes are all specifically coded to contribute to different functions of the body and brain, so any impact on epigenetic processes due to drug exposure is concerning, especially during a critical developmental window such as pregnancy.

Researchers found that significant changes involved genes associated with common neurobehavioral disorders, including autism spectrum disorder and attention deficit hyperactivity disorder. These conditions are linked to adverse health outcomes in childhood and adolescence, including poorer memory and verbal reasoning skills, and increased hyperactivity, impulsivity and inattention.

The research team hopes findings from this study will add to the limited existing literature on THC use during pregnancy, and help guide patient counselling and public health polices focused on cannabis in the future.

“It’s not common practice for providers to discuss cannabis use with patients who are pregnant or trying to conceive,” said the study’s corresponding author, Jamie Lo, MD, MCR, associate professor of obstetrics and gynaecology (maternal-foetal medicine) at OHSU. “I hope our work can help open up a broader dialogue about the risks of cannabis use in the preconception and prenatal period, so we can improve children’s health in the long run.”

Source: Oregon Health & Science University

Categories : CancerTags :

Defeating Cancer Cells by Knocking out their Extra Chromosomes

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Chromosomes. Credit: NIH

Most cancer cells are aneuploid, having extra chromosomes, and they depend on those chromosomes for tumour growth, a new study in the journal Science reveals. Eliminating them prevents the cells from forming tumours, which suggests that selectively targeting extra chromosomes may lead to a new form of cancer treatment which could spare healthy tissue which has the typical 23 pairs.

“If you look at normal skin or normal lung tissue, for example, 99.9% of the cells will have the right number of chromosomes,” said senior study author Jason Sheltzer, assistant professor of surgery at Yale School of Medicine. “But we’ve known for over 100 years that nearly all cancers are aneuploid.”

However, it was unclear what role extra chromosomes played in cancer, such as whether they cause cancer or are caused by it.

“For a long time, we could observe aneuploidy but not manipulate it. We just didn’t have the right tools,” said Sheltzer. “But in this study, we used the gene-engineering technique CRISPR to develop a new approach to eliminate entire chromosomes from cancer cells, which is an important technical advance. Being able to manipulate aneuploid chromosomes in this way will lead to a greater understanding of how they function.”

Using their newly developed approach, which they dubbed Restoring Disomy in Aneuploid cells using CRISPR Targeting (ReDACT), the researchers targeted aneuploidy in melanoma, gastric cancer, and ovarian cell lines. Specifically, they removed an aberrant third copy of the long portion, or ‘q arm’, of chromosome 1, which is found in several types of cancer, is linked to disease progression, and occurs early in cancer development.

“When we eliminated aneuploidy from the genomes of these cancer cells, it compromised the malignant potential of those cells and they lost their ability to form tumours,” said Sheltzer.

Based on this finding, the researchers proposed cancer cells may have an ‘aneuploidy addiction’ – a discovery that eliminating oncogenes, which can turn a cell into a cancer cell, disrupts cancers’ tumour-forming abilities. This finding led to a model of cancer growth called ‘oncogene addiction’.

When investigating how an extra copy of chromosome 1q might promote cancer, the researchers found that multiple genes stimulated cancer cell growth when they were overrepresented – because they were encoded on three chromosomes instead of the typical two.

This overexpression of certain genes also pointed the researchers to a vulnerability that might be exploited to target cancers with aneuploidy.

Previous research has shown that a gene encoded on chromosome 1, known as UCK2, is required to activate certain drugs. In the new study, Sheltzer and his colleagues found that cells with an extra copy of chromosome 1 were more sensitive to those drugs than were cells with just two copies, because of the overexpression of UCK2.

Further, they observed that this sensitivity meant that the drugs could redirect cellular evolution away from aneuploidy, allowing for a cell population with normal chromosome numbers and, therefore, less potential to become cancerous. When researchers created a mixture with 20% aneuploid cells and 80% normal cells, aneuploid cells took over: after 9 days, they made up 75% of the mixture. But when the researchers exposed the 20% aneuploid mixture to one of the UCK2-dependent drugs, the aneuploid cells comprised just 4% of the mix nine days later.

“This told us that aneuploidy can potentially function as a therapeutic target for cancer,” said Sheltzer. “Almost all cancers are aneuploid, so if you have some way of selectively targeting those aneuploid cells, that could, theoretically, be a good way to target cancer while having minimal effect on normal, non-cancerous tissue.”

More research needs to be done before this approach can be tested in a clinical trial. But Sheltzer aims to move this work into animal models, evaluate additional drugs and other aneuploidies, and team up with pharmaceutical companies to advance toward clinical trials.

“We’re very interested in clinical translation,” said Sheltzer. “So we’re thinking about how to expand our discoveries in a therapeutic direction.”

Source: Yale University