Common strength ‘genes’ identified for first time

cjb250 — Wed, 12 Jul 2017 09:28:41 +0000

̽��ֱ��researchers used data on hand grip strength from more than 140,000 participants in the UK Biobank study, combined with 50,000 additional individuals from the UK, Netherlands, Denmark and Australia, to identify sixteen common genetic variants that are associated with muscle strength.

Dan Wright, joint first author on this paper and a PhD student at the Medical Research Council Epidemiology (MRC) Unit at the ̽��ֱ�� of Cambridge, said: “ ̽��ֱ��very large number of individuals participating in UK Biobank provides a powerful resource for identifying genes involved in complex traits such as muscle strength, and helps us understand their underlying biology and its relevance to health.”

Many of these variants were located within or near to genes known to play a role in biological processes highly relevant to muscle function, including the structure and function of muscle fibres, and the communication of the nervous system with muscle cells.

Mutations in some of the genes highlighted are also known to be associated with severe monogenic syndromes – conditions caused by a single genetic mutations – characterised by compromised muscle function. This demonstrates that genetic variation in genes which cause serious muscular conditions may also influence differences in strength in the general population.

Dr Robert Scott, who co-led the study with colleagues from the MRC Epidemiology Unit, said: “While we have long suspected a role for genetics in the variation in muscle strength, these findings give the first insights into some of the specific genetic variants that underpin variation in strength.

“These could be important steps towards identifying new treatments to prevent or treat muscle weakness.”

Hand grip strength has been reported to be associated with many health outcomes, including risk of mortality, cardiovascular disease, and fracture – although it has been unclear whether variation in strength actually causes these outcomes, or simply reflects underlying disease processes.

Using the sixteen genetic variants identified for strength, the researchers were able to investigate the hypothesised causal link between strength and these adverse health outcomes. Their study found no evidence that lower strength causally increases risk of death or cardiovascular disease, but they did find evidence that higher muscular strength reduces risk of fracture, supporting the use of strength training interventions as a strategy to reduce risk of fractures.

Professor Nick Wareham, director of the MRC Epidemiology Unit and a senior author of the study, noted: “This work highlights the importance of muscle strength in the prevention of fractures and the complications which can often follow a fall.”

Reference
Willems, SM et al. Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness. Nature Communications; 12 July 2017; DOI: 10.1038/ncomms16015

Common genetic factors that influence muscle strength in humans have been identified for the first time in a study led by researchers from the ̽��ֱ�� of Cambridge and published today in Nature Communications.

̽��ֱ��very large number of individuals participating in UK Biobank provides a powerful resource for identifying genes involved in complex traits such as muscle strength

Dan Wright

Thomas Morris

Lose Weight and Gain Muscle

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Genetic approach could help identify side-effects at early stages of drug development

cjb250 — Wed, 01 Jun 2016 18:00:33 +0000

̽��ֱ��technique involves identifying genetic variants that mimic the action of a drug on its intended target and then checking in large patient cohorts whether these variants are associated with risk of other conditions, such as cardiovascular disease.

When developing a new drug for market, pharmaceutical companies must not only demonstrate that it is effective at treating a particular condition, but also that the drug does not have any adverse side-effects in patients. For example, the Food and Drug Administration, which approves all new medicines for use in the USA, has defined that any new anti-diabetic medicines need to demonstrate cardiovascular safety. However, in many cases adverse safety profiles do not become apparent until late in the drug development process, by which point millions – possibly even billions – of pounds will have been invested.

In a study published today in the journal Science Translational Medicine, scientists have provided a proof of concept that it is possible to use genetic analyses to demonstrate systematically at a very early stage whether a drug will alter the risk of developing other conditions.

A major class of anti-diabetic therapies are those known as glucose-lowering glucagon-like peptide-1 receptor (GLP1R)-agonists. These drugs bind to the GLP-1 receptor (which is encoded by the GLP1R gene) to increase insulin production, helping reduce levels of blood sugar. However, the cardiovascular safety, of this class of agents, including the risk of heart disease for example, remains unknown.

By analysing genetic variations in DNA encoding drug targets for type 2 diabetes and obesity in almost 12,000 individuals, the researchers identified a variant in the GLP1R gene that was associated with lower fasting glucose and a lower risk of type 2 diabetes – in other words, the variant appeared to mimic the action of the diabetes drugs. They confirmed this result in a further 40,000 individuals.

̽��ֱ��researchers then used genetic data available through an international data-sharing consortium to study the association of that same variant with coronary heart disease in almost 62,000 individuals with coronary heart disease and over 160,000 controls. In fact, they found that the variant actually reduced the risk of heart disease. Long-term large-scale randomised controlled clinical trials to evaluate the cardiovascular safety of GLP1R-agonists are underway and results from a large trial are scheduled to be released later this month.

“This further suggests that human genetics can support the development of new therapies, and can offer insights into their safety profile early in the development process,” says Dr Robert Scott from the Medical Research Council (MRC) Epidemiology Unit at the ̽��ֱ�� of Cambridge, the study’s first author.

Professor Nick Wareham, Director of the MRC Epidemiology Unit, added: “These findings suggest that beyond their effectiveness in treating diabetes, these drugs may have the added benefit of lowering risk of heart disease.”

“Researching and developing new medicines is a lengthy, expensive and risky journey, and any insights we can gain in to the processes of the body related to disease could help improve our ability to succeed,” says Dr Dawn Waterworth, joint senior author from GSK. “By pooling our resources and expertise in collaborations like this one with Cambridge ̽��ֱ��, we believe there’s an opportunity to expand our knowledge of disease biology, which in turn could help reduce the risk of late-stage failures and accelerate the development of innovative new treatments for patients.”

̽��ֱ��study was primarily funded by GSK and the Medical Research Council.

Reference
Scott, R et al. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease. Sci Trans Med; 2 June 2016; DOI: 10.1126/scitranslmed.aad3744

An approach that could reduce the chances of drugs failing during the later stages of clinical trials has been demonstrated by a collaboration between the ̽��ֱ�� of Cambridge and pharmaceutical company GlaxoSmithKline (GSK).

This further suggests that human genetics can support the development of new therapies, and can offer insights into their safety profile early in the development process

Robert Scott

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Diabetes

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Common strength ‘genes’ identified for first time

Genetic approach could help identify side-effects at early stages of drug development