Day: November 22, 2022

Genetic Links between Traits and Diseases may be Inflated

Genetics
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Many estimates of how strongly traits and diseases share genetic signals may be inflated, according to a new study published in Science that indicates current methods for assessing genetic relationships between traits fail to account for mating patterns.

With genome sequencing technology, scientists have been seeking out the genetic associations between traits and disease risk, hoping to find clues in treating diseases. However, UCLA researchers said their new study cautions against relying too much on genetic correlation estimates. They say that such estimates are confounded by non-biological factors more than has been previously appreciated.

Genetic correlation estimates typically assume that mating is random. But in the real world, partners tend to pair up because of many shared interests and social structures. As a result, some genetic correlations in previous work that have been attributed to shared biology may instead represent incorrect statistical assumptions. For example, previous estimates of genetic overlap between body mass index (BMI) and educational attainment are likely to reflect this type of population structure, induced by “cross-trait assortative mating,” or how individuals of one trait tend to partner with individuals of another trait.

The study authors said genetic correlation estimates deserve more scrutiny, since these estimates been used to predict disease risk, glean for clues for potential therapies, inform diagnostic practices, and shape arguments about human behaviour and societal issues. The authors said some in the scientific community have placed too much emphasis on genetic correlation estimates based on the idea that studying genes, because they are unalterable, can overcome confounding factors.

“If you just look at two traits that are elevated in a group of people, you can’t conclude that they’re there for the same reason,” said lead author Richard Border, a postdoctoral researcher in statistical genetics at UCLA. “But there’s been a kind of assumption that if you can track this back to genes, then you would have the causal story.”

Based on their analysis of two large databases of spousal traits, researchers found that cross-trait assortative mating is strongly associated with genetic correlation estimates and plausibly accounts for a “substantial” portion of genetic correlation estimates.

“Cross-trait assortative mating has affected all of our genomes and caused interesting correlations between DNA you inherit from your mother and DNA you inherit from your father across the whole genome,” said study co-author Noah Zaitlen, professor at UCLA Health.

The researchers also examined genetic correlation estimates of psychiatric disorders, which have sparked debate in the psychiatric community because they appear to show genetic relationships among disorders that seemingly have little similarity, such as attention-deficit hyperactivity disorder and schizophrenia. The researchers found that genetic correlations for a number of unrelated traits could be plausibly attributed to cross-trait assortative mating and imperfect diagnostic practices. On the other hand, their analysis found stronger links for some pairs of traits, like anxiety disorders and major depression, suggesting that there truly is at least some shared biology.

“But even when there is a real signal there, we’re still suggesting that we’re overestimating the extent of that sharing,” Border said.

Source: University of California – Los Angeles Health Sciences

Anti-hyperglycaemic Drugs Raise or Lower MS Risk Depending on Age

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A new study published in the journal Heliyon found that people older than 45 whose Type 2 diabetes (T2D) was treated with anti-hyperglycaemic drugs had an increased risk of multiple sclerosis (MS), especially women, while the reverse was true in under 45s.

“Our findings reinforce the need for a precision medicine approach to preventing MS in these vulnerable populations,” said lead researcher Kathleen Rodgers, PhD, associate director of translational neuroscience at the Center for Innovation in Brain Science.

Multiple sclerosis (MS) is an unpredictable autoimmune neurological disorder that affects the central nervous system and leads to severe physical and cognitive disability. It is estimated that more than 2.8 million worldwide are living with MS.

For people with T2D, growing evidence links metabolic disorders and MS through a common driver of increased autoimmunity. This brings into question the impact of anti-hyperglycaemic therapeutics used to treat T2D, including insulin, on the incidence of MS.

“Previous research has shown a neuroprotective effect of anti-hyperglycaemic medications in Alzheimer’s disease and other related dementias,” Dr Rodgers said. “For MS, we wanted to further examine age and sex differences, particularly among men and women under 45 with Type 2 diabetes.”

They found that men older than 45 years old had a slightly significant increase of MS risk and women older than 45 years exhibited a significant increase in MS incidence after anti-hyperglycaemic exposure. In addition to age differences, the risk analysis by drug class showed that exposure to insulin in patients older than 45 years old was associated with a greater increased risk compared with other therapies.

In patients younger than 45, anti-hyperglycaemic exposure was protective against the development of MS.

The study drew on a US-based insurance claims database of 151 million participants to identify more than 5 million patients with a diagnosis of T2D and either early-onset or late-onset MS. Researchers segmented the data by age – T2D diagnosis before or after age 45 – and sex to decode the factors driving MS risk in both populations, especially in women over 45 years of age.

Source: University of Arizona Health Sciences

Supreme Court of Appeal Reverses Controversial Ivermectin Ruling

Gavel
Photo by Bill Oxford on Unsplash

The Supreme Court of Appeal (SCA) has set aside a controversial supervisory order, granted in April 2021, compelling the South African Health Products Regulatory Authority (SAHPRA) to report back to court every three months on access to ivermectin for use in the treatment of COVID patients.

The court has ruled that there was no evidence to justify the order made by Pretoria High Court Judge Cassim Sardiwalla, that affected parties had not asked for the order, and that they had not been heard before he made it.

The judge had also failed to provide his reasons for making it, the court said.

The issue has its genesis in four applications, one by the African Christian Democratic Party in 2021 against SAHPRA seeking access to ivermectin for the treatment of COVID.

At that time, SAHPRA, which was wary of its use saying there was no reliable research to prove its efficacy, had already put in place its “controlled compassionate use” programme in response to reports of illicit ivermectin-containing products entering the South African market. The programme was stopped in May this year.

In terms of that programme, permission was granted to five importers of unregistered oral solid dosage forms of ivermectin. Health facilities were permitted to hold bulk stock but individual applications were still required. SAPHRA said it would monitor its use.

The ACDP and others approached the court for orders directing SAHPRA to remove restrictions and do “all things necessary to regulate and ensure the manufacture” of ivermectin until such time as clinical evidence demonstrated that it was not effective in the treatment of COVID.

The matter was settled along the same lines as SAHPRA’s programme.

But Judge Sardiwalla, in making the settlement agreement an order of court, also granted a “supervisory order”, putting SAHPRA under his judicial authority in respect of ivermectin.

SAHPRA and the Minister of Health applied for and were granted leave to appeal the order to the SCA.

Read the full judgment here

In heads of argument before the SCA, SAHPRA said its appeal concerned the propriety of the order directing an organ of state to report back to court and be subject to judicial supervision where the dispute had been settled and there was no evidence at all that SAHPRA and the minister would not comply with the settlement agreement.

“It was simply imposed without justification. The order constitutes a grave violation of the Constitution … it violates the rule of law, the right to a fair hearing and the principle of separation of powers,” it argued.

The judge, SAHPRA said, had improperly made findings on matters not in dispute and his written reasons for the supervisory order “do not constitute reasons at all”.

In the SCA ruling, Judge Clive Plaskett said Judge Sardiwalla had suggested to the parties that he “regarded himself as seized of all matters involving ivermectin” and had proposed the supervisory order.

Both SAHPRA and the minister indicated they would oppose this and filed further papers.

While the judge had indicated that he would hear the parties on 6 April 2021, his registrar had informed SAHPRA’s attorney that morning that he had made a decision, he would not hear arguments, and he would send his order to the parties shortly.

No reasons accompanied the order.

SAHPRA and the minister asked for reasons but when these were furnished, they made no mention of the supervisory order or why he granted it.

Judge Plaskett said the first difficulty with the order was that Judge Sardiwalla had not given SAHPRA and the minister a hearing despite knowing that they did not agree to it.

“He agreed to a hearing but inexplicably changed his mind. In these circumstances, an oral hearing was, without doubt, essential.

“Courts decide matters, particularly opposed matters, in open court and the exceptions to this rule are limited.”

Judge Plaskett said the fact that the order had not been applied for by any party required that it be set aside.

He said, further, there was a complete absence of evidence to justify it.

“Important as supervisory orders may be in appropriate cases, the granting of this type of relief must be carefully considered – and justified on the facts – particularly because of its separation of powers implications.

“In this case, not only was there no evidence as to the necessity of a supervisory order but the fact that SAHPRA and the minister had settled the matter and agreed to an order suggests that there was probably no necessity for one.

“Had he allowed the parties to argue the matter, he would have been informed of the separation of powers problem …

“Finally, it strikes me as telling that the reasons he furnished made no mention of the supervisory order – and this despite being pertinently asked to furnish reasons on this very issue,” Judge Plaskett said, upholding the appeal, and setting aside the order.

The ACDP originally opposed SAHPRA’s appeal but shortly before the SCA hearing, it withdrew its opposition on the basis that no cost order would be made against it. The SCA therefore did not order costs.

The ivermectin programme was stopped in May this year.

Republished from GroundUp under a Creative Commons Attribution-NoDerivatives 4.0 International License.

Source: GroundUp

‘Thor’ Actor Takes a Break from Acting after Alzheimer’s Gene Discovery

Actor Chris Hemsworth. Credit: Gage Skidmore / Wikimedia Commons

Actor Chris Hemsworth has announced that he is stepping back from acting in order to focus on preventative measures for Alzheimer’s disease.

The 39-year-old star of ‘Thor’ told Vanity Fair that genetic testing had confirmed that he had two pairs of a gene, APOE4. which is highly predictive of developing Alzheimer’s. About one in four have a single copy while 2–3% carry two copies of the gene.

The reason APOE4 increases Alzheimer’s risk isn’t not well understood. The APOE protein helps carry cholesterol and other types of fat in the bloodstream. Recent studies suggest that problems with brain cells’ ability to process lipids may play a key role in Alzheimer’s and related diseases.

Lipid imbalances can impair many of a cell’s essential processes. This includes creating cell membranes, moving molecules within the cell, and generating energy.

Hemsworth had made the discovery while making the TV series ‘Limitless‘, in which he engages in a variety of activities to push the limits of his own body and mind and explores ways of extending the lifespan.

“My concern was I just didn’t want to manipulate it and overdramatise it, and make it into some sort of hokey grab at empathy, or whatever, for entertainment,” said Hemsworth. “It’s not like I’ve been handed my resignation.”

He emphasises that he is thankful at having made the discovery, as it has made him more appreciative of his life, and it now means he can now take steps to protect his health.

Fortunately, research suggests that there are lifestyle changes that may offer preventative effects for APOE4 carriers, such as reducing stress and getting regular exercise – though the latter is unlikely to be a problem for the already athletic actor. Dietary measures include various low-carbohydrate diets (including ketogenic diets), regular portions of oily fish, cruciferous vegetables and abstaining from alcohol.

Supplements with potential benefits include DHA, quercetin, resveratrol, vitamin D3, vitamin K2, B-vitamin complex and possibly lithium.

Scientists Coax CNS Axons into Regenerating

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Severed axons are unable to regenerate, which means that central nervous system (CNS) injuries such as to the spinal cord, can result in permanent loss of sensory and motor function. Presently, there are very limited options to help these patients regain their motor abilities. In mice, researchers have found that deleting a certain gene can cause axons to regrow. The results have recently been published in the scientific journal Neuron.

In a study using mice, a research team led by Associate Professor Kai Liu found that the deletion of PTPN2, a phosphatase-coding gene, in neurons can prompt axons to regrow. Combination with the type II interferon IFNγ, can accelerate the process and increase the number of axons regenerated.

Unlike the CNS, peripheral nerves have a greater ability to regrow and repair by themselves after injury. Scientists have yet to fully understand the relationship between this self-repair and the intrinsic immune mechanism of the nervous system. Thus, the team aimed to resolve how immune-related signalling pathways affected neurons after injury, and whether they could enhance axonal regeneration directly.

This study investigated whether the signalling pathway IFNγ-cGAS-STING had any role in the regeneration process of peripheral nerves. Researchers found that peripheral axons could directly modulate the immune response in their injured environment to promote self-repair after injury.

In previous research, Prof Liu’s team had already demonstrated that elevating the neuronal activity and regulating the neuronal glycerolipid metabolism pathway could  boost axon regenerative capacity. The current study is providing further insights into the search of treatment solutions for challenging conditions such as spinal cord injuries, with one possible option being the joining of several types of different signalling pathways.

Source: EurekAlert!