A Mediterranean diet is characterised by high intake of plant-based foods (fruit, vegetables, nuts and cereals) and olive oil, moderate intake of fish and alcohol and low intake of dairy products and red and processed meat.  Studies have shown that many of these dietary components of the Mediterranean diet play an important role in bone and muscle health.  We proposed that the additive effects of these individual dietary components would have a greater impact on musculoskeletal health.  The aim of the study was therefore to examine associations between adherence to a Mediterranean diet and key indicators of bone and muscle status, including fracture incidence, bone density and muscle mass. [Read more…]

Previous research has shown that physical activity is good for our bodies and minds, and spending too much time sedentary (sitting) tends to do the opposite for our health.

Physical activity is increasingly being measured using accelerometry devices, which track intensity and duration of body movement. The use of accelerometers is an advance over the previously used self-report methods, which are prone to measurement error from imprecise and biased recall, and can thereby mask the true nature and magnitude of associations.

Our study examined whether prior activity patterns were associated with later health outcomes. The large sample of detailed data on accelerometer-measured physical activity in EPIC-Norfolk, along with incident disease data and a long follow-up duration made EPIC-Norfolk an ideal study for this work. [Read more…]

Having genetically higher testosterone levels increases the risk of metabolic diseases such as type 2 diabetes in women, while reducing the risk in men. Higher testosterone levels also increase the risks of breast and endometrial cancers in women, and prostate cancer in men.

The findings come from the largest study to date on the genetic regulation of sex hormone levels, published today in Nature Medicine and led by researchers from the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge and the University of Exeter. Despite finding a strong genetic component to circulating testosterone levels in men and women, the authors found that the genetic factors involved were very different between the sexes.

The team used genome wide association studies (GWAS) in 425,097 UK Biobank participants to identify 2,571 genetic variations associated with differences in the levels of the sex hormone testosterone and its binding protein sex-hormone binding globulin (SHGB).

The researchers verified their genetic analyses in additional studies, including the EPIC-Norfolk study and Twins UK, and found a high level of agreement with their results in UK Biobank.

The team next used an approach called Mendelian randomisation, which uses naturally occurring genetic differences to understand whether known associations between testosterone levels and disease are causal rather than correlative. They found that in women, genetically higher testosterone increases the risks of type 2 diabetes by 37 per cent, and polycystic ovary syndrome (PCOS) by 51 per cent.  However, they also found that having higher testosterone levels reduces T2D risk in men by 14 per cent. Additionally, they found that genetically higher testosterone levels increased the risks of breast and endometrial cancers in women, and prostate cancer in men.

Dr John Perry from the MRC Epidemiology Unit at the University of Cambridge, and joint senior author on the paper, says:

Our findings that genetically higher testosterone levels increase the risk of PCOS in women is important in understanding the role of testosterone in the origin of this common disorder, rather than simply being a consequence of this condition.” 

Likewise, in men testosterone-reducing therapies are widely used to treat prostate cancer, but until now it was uncertain whether lower testosterone levels are also protective against developing prostate cancer. Our findings show how genetic techniques such as Mendelian randomisation are useful in understanding of the risks and benefits of hormone therapies.”

Dr Katherine Ruth, of the University of Exeter, one of the lead authors of the paper, added:

Our findings provide unique insights into the disease impacts of testosterone. In particular they emphasise the importance of considering men and women separately in studies, as we saw opposite effects for testosterone on diabetes. Caution is needed in using our results to justify use of testosterone supplements, until we can do similar studies of testosterone with other diseases, especially cardiovascular disease.”

• Full paper: Katherine S Ruth, Felix R Day, Jessica Tyrrell et al. Using human genetics to understand the disease impacts of testosterone in men and women. Nature Medicine; 10 February 2020; DOI: 10.1038/s41591-020-0751-5

Meeting minimum public health recommendations could prevent nearly one in two deaths linked to physical inactivity

Keeping physically active or becoming more active during middle and older age is associated with a lower risk of death, regardless of past activity levels or existing health conditions, suggests a large UK study published today by The BMJ.

The new findings indicate that at the population level, meeting and maintaining at least the minimum public health recommendations (equivalent to 150 minutes per week of moderate-intensity physical activity) would potentially prevent 46% of deaths associated with physical inactivity. [Read more…]

People who are less likely to put on excess fat around their hips due to their genes are at higher risk of type 2 diabetes and heart attacks, according to a new study led by scientists from the MRC Epidemiology Unit at the University of Cambridge.

While it has long been recognised that an “apple-shaped” body is associated with an increased risk of diabetes and heart disease, the new research sheds light on the specific genetics linked to this body shape and the potential mechanisms behind the increased risk. The researchers suggest that their findings, published in JAMA: the Journal of the American Medical Association, may help to better identify individuals at risk of developing these conditions and inform their subsequent treatment.

The researchers studied the genetic profiles of over 600,000 participants from several large UK and international studies – including the UK Biobank, Fenland, EPIC-Norfolk, and EPIC-Interact – and identified over 200 genetic variants that predispose people to a higher waist-to-hip ratio, a measure of the “apple shaped” body. Using this data, the researchers identified two specific groups of genetic variants that increased waist-to-hip ratio – one exclusively via lower hip fat and the other exclusively via higher waist (abdominal) fat. [Read more…]

New drugs that lower levels of triglycerides (a type of fat) in blood could further reduce the risk of heart attack when added to statins. These new drugs, which are in various stages of development, could also reduce blood glucose levels and the risk of diabetes, according to a new genetic study from the Medical Research Council Epidemiology Unit at the University of Cambridge.

MRC scientists behind the research, published today in JAMA Cardiology, suggest these new drugs – lipoprotein lipase enhancers – could be paired with statins, the current gold standard for high cholesterol treatment, or other cholesterol lowering agents. Their findings, which stem from a type of genetic study which aims to simulate a clinical trial, hold promise for clinicians and pharmaceutical companies that are considering testing the efficacy of these novel drugs.

Dr Luca A. Lotta, Senior Clinical Investigator at the MRC Epidemiology Unit, said:

Our study suggests that these new triglyceride-lowering agents could give additional benefits to patients with heart disease when added to statins. This combination could prevent more heart attacks as well as reduce the risk of developing type 2 diabetes.”

Heart disease is a significant problem in the UK, tied to more than a quarter of all deaths in the country, according to 2018 estimates. One of the major factors leading to heart disease is high levels of low density lipoprotein or LDL cholesterol, often referred to as “bad cholesterol”.

Statins are widely prescribed to lower LDL levels and are effective at preventing heart disease. Some people who are treated with statins will still encounter heart attacks, which has been partly linked to raised levels of triglycerides in their blood.

Normally, our bodies can break down triglycerides with a protein called lipoprotein lipase or LPL. In recent years, scientists and drug developers have tapped into this, developing several new agents that enhance the activity of this enzyme. However, these drugs are still in pre-clinical stages.

In theory, these new heart drugs could be used in combination with statins and other cholesterol-lowering agents, but there hasn’t been a large-scale trial to show their efficacy. MRC scientists used genetic data to gain insights into their likely efficacy and safety in advance of a large-scale trial.

The new research studied the genetics of some 400,000 people from the UK Biobank, EPIC-InterAct, and EPIC-Norfolk studies. Scientists used an approach called Mendelian randomisation, which uses naturally occurring genetic differences to simulate the effects of a clinical trial, to study the likely effects of statins and these novel LPL-enhancing drugs.

Some people have a variation in their DNA that naturally increases the effectiveness of LPL, mimicking the effect that would be caused if the LPL-enhancing drugs were used.

In this study, people who carried both triglyceride-lowering DNA variants in the LPL gene and cholesterol-lowering variants in several other genes (simulating the protective effect of statins) had a lower risk of heart disease compared with people with only one of either of these sets of DNA variants.

The researchers believe these drugs could mitigate some of the potential side effects of statins, too. For some people, statins can increase the risk of developing type 2 diabetes – 50 to 100 new cases for every 10,000 patients treated. The scientists found that those with LPL gene variants had a lower risk of type 2 diabetes in all study groups, suggesting that these new drugs may improve blood glucose control when paired with statins.

Dr Lotta said:

We’re using genetics to gain insight and help to predict the likely result of future trials. Studies that simulate clinical trials are invaluable because large-scale trials are expensive, take years to conduct and considerable resources – scientists need strong evidence of a drug’s likelihood of success before it gets to the trial stage.”

Clinical trials are costly endeavours but emerging findings indicate the odds of successful drug development are increased when knowledge about these novel agents is bolstered by genetic studies. To empower these studies, the MRC, pharmaceutical companies, and other funders have invested in large genetic resources including the recent announcement of a consortium of companies to sequence the DNA of all participants of the UK Biobank, a study of 500,000 people from the general UK population.

• Read the full paper:Genetically-enhanced LPL mediated lipolysis, LDL cholesterol lowering alleles and risk of coronary disease and type 2 diabetes. Luca Lotta et al., JAMA Cardiology, 19 Sept 2018. DOI:10.1001/jamacardio.2018.2866

Summary

Glaucoma is the leading cause of irreversible blindness in the world. Raised intraocular pressure (IOP) is the most important modifiable risk factor for primary open-angle glaucoma (POAG). Yet the mechanism underling IOP regulation is not yet understood.  Prior to our study, genome-wide association studies (GWAS) had identified only a few genetic markers associated with IOP, explaining a tiny proportion of its variability.

We carried out a GWAS for IOP in over 100,000 European participants and identified 112 independent loci associated with IOP.  These genetic markers explained 17% of the variance of IOP, which is huge considering the daily variation in IOP in individuals and measurement error which affects IOP readings. [Read more…]

A study of over 85,000 men, led by researchers from the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge and deCODE genetics in Iceland, and published today in Nature Genetics, has uncovered key genetic factors that influence the rate at which men and women lose chromosomes from their cells as they age.

Cells in our body contain 23 pairs of chromosomes, including a pair of sex chromosomes that are either XX in females or XY in males, which contain all of our genes. These cells are constantly dividing to create new cells, an important biological process which can be prone to error. This can result in populations of cells having too few or too many chromosomes, a genetic feature termed aneuploidy. Understanding the biological processes that regulate normal cell growth has important implications for diseases such as cancers, which are underpinned by abnormalities of cell growth and errors in DNA replication and repair.

The study focussed on cells missing the Y chromosome, the most common genetic defect in circulating white blood cells. The Y chromosome has the smallest number of genes of any human chromosome, and its genes have a relatively restricted pattern of activity, so in most tissues its’ loss is better tolerated than that of other chromosomes. Previous studies have found that this defect increases with age, and up to one in five men over the age of 80 has detectable Y chromosome loss in their white blood cells. By measuring this in over 85,000 men, the researchers identified 19 gene regions which appear to regulate this defect. These analyses included genetic data from 67,000 men participating in UK Biobank, in addition to 18,000 men from the EPIC-Norfolk and deCODE studies.

Many of the identified genetic regions include genes with well-established roles in cancer and cell division, demonstrating the strength of the approach in identifying relevant genes. In addition, several genes with no prior link to cell division errors were identified, highlighting potentially novel pathways for further biological investigation.

Dan Wright, a PhD student from the MRC Epidemiology Unit who was the lead author on this study, said:

By exploiting the fact that cells can survive without a Y chromosome, we were able to identify genes that are associated with errors of cell division. This helps identify novel and potentially important biological pathways and targets for future studies of diseases such as cancer.”

The researchers also studied genetic data from over 96,000 women from the same studies. While loss of the X chromosome in women was found to be less common than loss of Y chromosome in men, it was predicted by the same 19 gene regions. This suggests that the identified genetic effects are not specific to men or to Y chromosome loss, but act more generally on maintaining chromosomes during normal cell division.

Smoking has been suggested as a cause of chromosome loss in circulating cells, although it was previously unclear if this is due to a direct causal effect of smoking or by unrelated confounding factors, for example socioeconomic status. Using the same genetic data, the researchers found evidence for a causal effect of smoking on Y chromosome loss.

Dr John Perry, also from the MRC Epidemiology Unit and senior author on the paper, noted that:

This study provides new insights into the effects of smoking on fundamental biological processes such as cell division. Whilst it is unclear to what extent mosaic chromosome loss is a mechanism linking smoking to cancer susceptibility, it is clear that the study of this phenomenon can highlight important biological pathways related to normal cell growth.”

• Read the full paper: “Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility” Daniel J. Wright, Felix R. Day, Nicola D. Kerrison, Florian Zink, Alexia Cardona, Patrick Sulem, Deborah J. Thompson, Svanhvit Sigurjonsdottir, Daniel F Gudbjartsson, Agnar Helgason, J. Ross Chapman, Steve P. Jackson, Claudia Langenberg, Nicholas J. Wareham, Robert A. Scott, Unnur Thorsteindottir, Ken K. Ong, Kari Stefansson and John R.B. Perry, Nature Genetics, 27 March 2017. DOI:10.1038/ng.3821

A large-scale genetic study has provided strong evidence that the development of insulin resistance – a risk factor for type 2 diabetes and heart attacks and one of the key adverse consequences of obesity – results from the failure to safely store excess fat in the body.

Overeating and lack of physical activity worldwide has led to rising levels of obesity and a global epidemic of diseases such as heart disease, stroke and type 2 diabetes. A key process in the development of these diseases is the progressive resistance of the body to the actions of insulin, a hormone that controls the levels of blood sugar. When the body becomes resistant to insulin, levels of blood sugars and lipids rise, increasing the risk of diabetes and heart disease. However, it is not clear in most cases how insulin resistance arises and why some people become resistant, particularly when overweight, while others do not.

An international team led by researchers at the University of Cambridge studied over two million genetic variants in almost 200,000 people to look for links to insulin resistance. In an article published today in Nature Genetics, they report 53 regions of the genome associated with insulin resistance and higher risk of diabetes and heart disease; only 10 of these regions have previously been linked to insulin resistance.

The researchers then carried out a follow-up study with over 12,000 participants in the Fenland and EPIC-Norfolk studies, each of whom underwent a body scan that shows fat deposits in different regions of the body. They found that having a greater number of the 53 genetic variants for insulin resistance was associated with having lower amounts of fat under the skin, particularly in the lower half of the body.

The team also found a link between having a higher number of the 53 genetic risk variants and a severe form of insulin resistance characterized by loss of fat tissue in the arms and legs, known as familial partial lipodystrophy type 1. Patients with lipodystrophy are unable to adequately develop fat tissue, and often develop diabetes and heart disease as a result.

Our study provides compelling evidence that a genetically-determined inability to store fat under the skin in the lower half of the body is linked to a higher risk of conditions such as diabetes and heart disease,” says Dr Luca Lotta, first author on the paper and a Clinical Career Development Fellow at the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge. “Our results highlight the important biological role of peripheral fat tissue as a deposit of the surplus of energy due to overeating and lack of physical exercise.”

In follow-up experiments in mouse cells, the researchers were also able to show that suppression of several of the identified genes (including CCDC92, DNAH10 and L3MBTL3) results in an impaired ability to develop mature fat cells.

We’ve long suspected that problems with fat storage might lead to its accumulation in other organs such as the liver, pancreas and muscles, where it causes insulin resistance and eventually diabetes, but the evidence for this has mostly come from rare forms of human lipodystrophy,” adds Professor Sir Stephen O’Rahilly, Director the MRC Metabolic Diseases Unit and Metabolic Research Laboratories at the University of Cambridge. “Our study suggests that these processes also take place in the general population.”

Overeating and being physically inactive leads to excess energy, which is stored as fat tissue. This new study suggests that among individuals who have similar levels of eating and physical exercise, those who are less able store the surplus energy as fat in the peripheral body, such as the legs, are at a higher risk of developing insulin resistance, diabetes and cardiovascular disease than those who are able to do so.

People who carry the genetic risk variants that we’ve identified store less fat in peripheral areas,” says Professor Nick Wareham, Director of the MRC Epidemiology Unit. “But this does not mean that they are free from risk of disease, because when their energy intake exceeds expenditure, excess fat is more likely to be stored in unhealthy deposits. The key to avoiding the adverse effects is the maintenance of energy balance by limiting energy intake and maximising expenditure through physical activity.”

These new findings may lead to future improvements in the way we prevent and treat insulin resistance and its complications. The researchers are now collaborating with other academic as well as industry partners with the aim of finding drugs that may reduce the risk of diabetes and heart attack by targeting the identified pathways.

The research was mainly funded by the Medical Research Council, with additional support from the Wellcome Trust.

• Read the full paper: Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance, Luca A. Lotta et al., Nature Genetics, 14 November 2016. DOI:10.1038/ng.3714