Researchers identify key genes involved in chronic back pain

A team of researchers from around the world, led by TwinsUK’s Professor Frances Williams, has discovered three new genes linked to the development of chronic back pain. In a huge study of 440,000 people, ranging from 50 to 76 years old, the team studied the whole genome to look at genes that contribute to chronic back pain. They discovered that the genetics of back pain is very complex, with numerous different genes having an effect; however a group of three genes had a noticeably bigger effect.

The researchers had thought they would find that pain-related genes would be the main genes associated with chronic back pain. However, they instead found that the strongest link was with three genes involved in bone and intervertebral disc development. Crucially this suggests that degeneration of the spine influences chronic back pain, which is in line with previous TwinsUK research showing that spine degeneration predicts back pain episodes.

Spine degeneration is something that happens to us all as we age. The team hopes that further research into the three new genes will enable them to target new treatments to slow down the ageing process in the spine and therefore prevent long-term back pain.

Read more about this research on the King’s College London news pages, or read the open access paper, published in PLOS Genetics. This research has also been turned into an animation which you can view here.


Gut microbe diversity linked to lower arterial stiffness

New research from TwinsUK and the University of Nottingham has identified a link between gut microbe diversity and arterial stiffness.

Arterial stiffness, or hardening, happens naturally as we age and is a known risk factor for cardiovascular disease. The rate at which this hardening occurs varies from person to person.

The gut microbiome is implicated in various aspects of health, and has previously been linked to inflammation, which can increase the risk of developing heart disease.

Using data from 617 female twins, researchers found that gut microbiome diversity correlates with arterial stiffness; arterial stiffness is higher in women with lower diversity of healthy bacteria in the gut.

The researchers were also able to identify specific types of healthy bacteria that lowered the risk of arterial stiffening. These bacteria have previously been linked to a lower risk of obesity.

The results suggest that the gut microbiome could in future be used to identify those people at higher risk of a cardiovascular event in the absence of more traditional risk factors such as obesity or smoking.

This study was funded by the British Heart Foundation and MRC and was published by European Heart Journal.

New genes implicated in whether skin will burn in the sun

Researchers at TwinsUK have identified ten new genetic regions involved in whether a person is likely to tan or burn. These new regions also suggest who may be more likely to develop skin cancer.

Sunburn is already a known risk factor for skin cancer, the most common type of cancer in Europe, but whether a person’s skin will burn or tan varies widely from person to person.

In the largest study to date of skin’s tendency to tan or burn, TwinsUK researchers Mario Falchi and Alessia Visconti of King’s Department of Twin Research, in a collaborative effort with colleagues from across the world, analysed genetic data from 176,678 individuals of European ancestry. As well as identifying new genetic regions that indicate whether or not a person will tan or burn, one of these regions, which has previously been associated with melanoma, may directly increase the risk of cancer by reducing the ability of the skin to tan.

The study’s results have doubled the number of genetic regions known to be involved in tanning versus burning. Their discovery paves the way for further research to explore how the genetic regions contribute to the risk of skin cancer.

This research is published in Nature Communications. Find out more and read the paper here.

More than 100 genes determine hair colour

Dr Pirro Hysi and a group of researchers from Kings’s College London and Erasmus MC University Medical Center Rotterdam have discovered 124 genes that play a major role in human hair colour. The study is the largest of its kind, using DNA data and self-reported hair colour information from nearly 300,000 people.

Previous studies have found that much of the variation in human hair colour is down to genetics, with around a dozen known genes, but this study largely completes the knowledge gap of which genes control hair colour. Around 100 of the genes the team discovered were not previously known to contribute to pigmentation. These new genes have also allowed the team to predict hair colour much more accurately than before.

The study is the largest genetic study on pigmentation ever undertaken and could advance our knowledge of diseases that are linked to pigmentation, such as skin cancer. The results could also be applied to forensic science.

Read the paper, published in Nature Genetics.

Genes affect fat deposition and Type 2 diabetes risk

A new paper from Dr Kerrin Small and her team has found that a variant of the KLF14 gene, previously identified in earlier research by the same group, not only changes where fat is deposited (on the hips versus on the waist), but that it also affects the generation of new fat cells.

Using biopsy and blood samples from 856 female twins, fat biopsies from the Oxford BioBank and genetic data from the UK Biobank, their latest study found that variations of the KLF14 gene also makes it harder to generate new fat cells, leaving carriers of the gene with fewer, larger fat cells that are less efficient. These less efficient fat cells reduce the body’s sensitivity to insulin and suggests that there is an increased chance of developing Type 2 diabetes.

Even more strikingly, these effects are specific to females; the researchers found that the gene only acts in women who inherit the diabetes-associated version from their mother. These women had around a 30% higher chance of developing diabetes than those without the diabetes-associated version.

These exciting results mean that we now have such a detailed level of understanding of this variant of the KLF14 gene that we know where and how it acts in the body as well as who it acts in. The team hope that these results will allow them to understand why the gene variant only affects women’s chance of developing diabetes so that they can help develop better prevention and treatment options.

Read the paper, published in Nature Genetics.

Dietary omega-3 improves the diversity of gut bacteria

New research from TwinsUK, published in the Nature journal Scientific Reports last week suggests that including more dietary omega-3 fatty acids improves the diversity of bacteria found in our gut.

The study, carried out in 876 women from the TwinsUK cohort, looked at whether dietary intake of fatty acids affects the diversity of the gut microbiome. The authors found that the amount of omega-3 fatty acids correlates with improved bacterial diversity in the gut, and is specifically associated with “good” bacterial species. The effects of dietary omega-3 were also seen in metabolites produced by gut bacteria. Higher levels of beneficial compounds, including omega-3 itself as well as n-carbamyl glutamate (NCG) which has been linked to reduced gut inflammation in rats, were found in people with more omega-3 in their diets.

The findings suggest that we could improve our gut health through our diets and the team is now planning a new study to test whether giving omega-3 supplements might improve the diversity of gut bacteria in healthy volunteers.

The open access paper is available to read here.

Ideas that change healthcare: Our future growing older and what we can do now

By Dr Claire Steves

Our healthcare system faces myriad challenges in the next fifty years. We’ve been aware of our growing elderly population for many years, but so far little has been done to address the challenges this raises for the future of healthcare. Here, Dr Claire Steves lays out her vision of healthcare, and what we can do now to prevent current challenges becoming serious problems in the future.

This blog has been adapted from Claire’s speech at The King’s Fund’s Festival of Ideas event on 6th October 2017.

When asked to think about a way forward for healthcare, I think it’s first helpful to look back through the history of medicine. I like to think of medical history in three eras: the preservative, the diagnostic, and hopefully, in the future, the integrated era.

In the preservative era, alcohol was a key way of preserving water, reducing the risk of infection
In the preservative era, alcohol was a key way of preserving water, reducing the risk of infection

The first era of medicine: preservative
The premedical “preservative” era extends back for millennia. This era represents the majority of human history when the main health threats were starvation, and infection. Strategies that humans created then have had huge implications for human health now. Most important has been the use preservatives to avoid infection, and keep food and water fresh.

Our main healthcare resources to combat infection in the preservative era were salt for preserving meat, alcohol for fruit and most importantly water (if you had a liking for fermented products, you were much less likely to die of cholera!), and sugar, which was not only a preservative but also a valuable energy source. Our ancestors who chose these foods may have had a selective advantage, but that advantage is gone today.

Perhaps driven by this need to conserve energy, as adults we appear to have an increasing tendency to move as little as possible. As a mother of three boys, I’m intrigued that children have such an insatiable desire to move, and yet this seems to disappear as we age; with adult humans choosing energy conservation and sedentary lives.

Could it be that this preventative medicine and tendency to over eat and conserve energy means that we are programmed to prefer things that are no longer beneficial?

So, healthcare in the premedical, preservative era was preventative, practiced in the home by housewives and mothers. In industrial times, city planners became important, introducing water systems which improved sanitation. Then followed widespread use of antibiotics, the magic bullet of the 20th century. These two revolutions have contributed to the increase in our lifespan over the last 100 years.

“…over indulgence and a preference for moving as little as possible have impacts for healthcare”

But all medicine has side effects. The preservative era has left us with hangovers which we are still feeling today; over indulgence and a preference for moving as little as possible have impacts for healthcare. Emerging evidence that antibiotics have changed the microbes in our guts, with effects on a wide range of chronic conditions, suggests that even our medicines can leave us with new problems. These hangovers have particular relevance now that we are living much longer, and evidence suggests that these fractors are driving unhealthy ageing.

The second era of medicine: diagnostic
The healthcare service we have today has been built on the second era of medicine. I call this the era of the “unifying diagnosis”. This has been an era where we have honed the classification, diagnosis and treatment of specific diseases.

The massive advances in medicine have targeted single diseases or conditions and have been hugely successful in preventing and treating these diseases. The hospital has, for the most part been the central hub, and scientists, doctors and nurses have put the medicine into practice and the more specialised and focused the better.

These two eras of medicine – the preservative and the unifying diagnosis – have led to an increase in life expectancy, which has rocketed especially in the last 150 years. The slightly less good news, however, is that the average man now spends 16 years at the end of his life with functional limitation, and the average woman 19 years!

This means that sort of medicine costing the most, and with the biggest burden within our services has now changed. The main users of healthcare have also changed. The biggest burden of ill health is now shouldered by the oldest among us, and these people are not well served by the “unifying diagnotic” model.

“The biggest burden of ill health is now shouldered by the oldest among us, and these people are not well served by the [current] medical model”

The unsolved problem we are now facing has been called many names, most of them problematic: frailty, multimorbidity, Geriatric Giants. One thing is for sure, it’s no longer about ‘diagnosed cases’ and ‘controls’, but more about sliding scales with age. I particularly like the word “homeostenosis”.

Many of us are familiar with homeostasis – the ability to keep things in balance. Homeostenosis on the other hand is gradual reduction in the ability to keep things in balance, to the point where equilibrium is disturbed and the ability to function is lost. This process happens on multiple levels – physiologically, psychologically and socially.

So has the success of the unifying-diagnostic model of medicine, of diagnosis and treatment of specific diseases, revealed the problem that was laid down in the preservative pre-medical era? It seems that the institutions built during the diagnostic era don’t seem to be providing solutions which work. We need to ask ourselves: is our health service built to help people with multiple needs on multiple levels? This is what we need to focus on to reverse the side effects of our medical history.

“…is our health service built to help people with multiple needs on multiple levels?”

We need to restructure our medical thinking, and move our services away from the “unifying diagnosis” and centralised healthcare. We also need to counter those things that are driving the phenomenon of frailty: caloric over indulgence, a preference for moving as little as possible, and, probably, excessive antibiotic use. We must aim our research at understanding and avoiding homeostenosis.

Immediate challenges
In my view, we have three key challenges to overcome in the near future to ensure that healthcare meets the demands of the future:

We need to change how we research the ageing process
A great deal has been invested in studying ageing using animal models, with the worm C. elegans, the fruit fly Drosophila, and the mouse having been put to great use in studying ageing, particularly lifespan. All three have highlighted insulin signalling pathways, and energy restriction as key to ageing. Mice have been very useful in showing the effects of physical activity. But animal models can only get us so far; they have perhaps been less helpful in studying the effects of alcohol and salt. These may be particular human problems!

Recently, there have been really exciting advances in animal research. Microbiota transplantation experiments in gnotobiotic mice, bred in sterile conditions with no gut microbes, are helping us to understand how our microbes may affect multiple physiologies simultaneously.

Despite these advances, there are two problems. Firstly, it’s not all about age, or living longer. We really should be focusing our efforts on maximising the amount of time we can live in good health, without frailty. To do this, animal models need to address the quality of ageing, not the quantity. Secondly, clinicians need to be directly involved in ageing research. Cardiology and cancer made their huge advances by ensuring that every consultant clinician had a research degree. In Geriatric Medicine (the biggest medical specialty) only 1 in 50 senior trainees have a research degree, and very few medical schools have a professor of Geriatric Medicine. This must change.

We need to encourage older adults to take part in research
It’s very difficult to engage and recruit frail older people in research. There are challenges with access to the research environment and there are risks associated with using interventions in those who are frail.

For example, I am involved in a multicentre study of two promising new treatments for sarcopenia – muscle wasting with ageing. We’re finding it almost impossible to recruit patients yet we urgently need to do the research to help translate geroscience – the study of the relationship between aging and age-related diseases – into the real world.

We need to address the social divides in ageing
There is a worrying divide where frail ageing is happening much more to the less well off. The functional difficulties associated with ageing are much more of a problem in the lowest socio-economic groups. And this is a problem that is getting worse, not better. We must ensure that any solutions we create reverse this health injustice.

All this is taking shape within a larger unsettled political landscape. Our health service and our research capability are being heavily threatened by our divorce from the European Union. This threat overshadows potential progress over the next fifty years, which we should not be shy of debating.

What are the assets at our disposal as we move to integrated healthcare?
If there is a poly pill, we already know what it is. There is already one clear key to health happiness and resilience: physical activity. But how do we get the whole population moving and remove our addiction to the combustion engine?

The information revolution means the structure of society no longer needs to focus on urban centres. Commuting no longer needs to dominate, and we can free up time for physical activity. Could we envisage a world where miles are minimised and foot travel is the preferred of interacting with our environment?

“If there is a poly pill, we already know what it is… physical activity”

For this to work physical activity needs to be both the most pleasant and most efficient way of doing things, both in work and in leisure, and must be embedded in every aspect of policy planning. We need to prioritise physical activity everywhere, from buildings to public spaces, from homes to offices. We also need physical activity to thrive in schools – it must be part of our way of life early on.

The second asset we have at our fingertips is the potential of personalised medicine. Here I’m talking about the possibility that we can use multi-omic technology, such as genomics, metabolomics, and metagenomics to provide medicine and prevention plans tailored to individuals.

For ageing, imagine that a person at that moment in their lives, perhaps at 40 or 50, when they start to realise that they are not invincible, that mortality will come also to them, and that perhaps they need to make some changes. Imagine they could have a series of tests that could show them how they are likely to age, and how that could change if they were to make some targeted lifestyle changes. Could this empower and motivate personal change?

This approach has huge potential, but we need to ensure that we do not widen existing health inequalities and that access to personalised medicine is available to everyone and anyone.

“…we need to ensure that … access to personalised medicine is available to everyone and anyone”

Our third potential asset is one we could use to reduce health injustice, or increase it. Social networks and big data are emerging as important fields of health research. Could we use these networks to target health education to reduce the health-economic divide?

If we can join social network “case finding” with personalised medicine using remote technologies, such as wearable tech and blood spot cards sent to doctors by post, we could imagine an entirely different world of preventative medicine. Social media is already being used by industry to target individuals – we’ve all seen personalised adverts on our computer screens. Can we do it in the NHS for the benefit of people’s health?

So where do we go from here?
Our lifespan is growing, in excess of our health span and the healthcare system we need to solve this issue is not the one we have come to rely on. We need to build translational ageing research, engage older adults in research, and counter the increasing health inequalities with age. Here I’ve outlined three key assets we can use to address these challenges: physical activity, personalised medicine and social networks. The time has come to use these assets to shape the healthcare system of the future. The third era of medicine must, like the first be an era of preventative medicine, but this time with fewer side effects!

World Alzheimer’s Day 2017: Q&A with Dr Claire Steves

Dr ClaiAlzheimer's day 2017_lead image 2re Steves is both a geriatrician as well as a gerontologist and is the principal investigator for ageing and frailty at the Department of Twin Research, researching health and fitness in older people. As a geriatrician, Claire specialises in dementia and delirium and focuses on people with complex problems that require specialist approaches to treatment.

September 21st marks World Alzheimer’s Day. We caught up with DTR researcher Dr Claire Steves to find out about early stage Alzheimer’s disease and her research into cognitive decline.

Many people are familiar with Alzheimer’s, but perhaps more so with the advanced stages of the disease. As a geriatrician you see patients in the earlier stages of Alzheimer’s – what are the symptoms?

When I see patients for the first time one of the most common things I find is that a relative has noticed they might keep repeating themselves a lot, saying the same thing over and over. It’s recent memory that goes first; perhaps they also can’t remember what they’ve had for dinner or can’t keep track of the TV. In contrast, memory of past events can be very good.

A common test we use is to show images of slightly less common things such as a camel or a rhinoceros. A person with early stage Alzheimer’s wouldn’t be able to name them.

Are there any challenges in diagnosing Alzheimer’s disease in its early stages?

Yes, it can be tricky: one issue is that when someone first goes to their GP with early symptoms they’ve probably been slowly developing Alzheimer’s for years. The real problem is that it can be hard to determine whether they do have Alzheimer’s or whether there’s something else going on. Do they have stress or anxiety, or some other medical condition, or might it be normal decline with age?

We can do detailed tests that look at how someone creates new memories by asking them to remember an item and its location. Joining these two things seems to predict Alzheimer’s early on. We can also use imaging or even take spinal fluid (a lumbar puncture) to look at the amounts of different proteins in the fluid around the brain.

One thing that’s often overlooked is delirium in older people who are have another illness. People with delirium become confused and maybe hallucinate. It can be very distressing for patients, family and carers and can be a real risk for falls or hitting out. We know that people who have delirium are more at risk of cognitive decline. We also know that we can prevent delirium by being careful with how we treat patients in hospital – it’s an unmet need. I follow these patients up when they’re better to see if they might have early stage Alzheimer’s.

Are there any treatments available to people with early stage Alzheimer’s?

The biggest thing that makes a difference is to understand what’s happening and find ways to cope with it in daily life, with help from family members or carers.

There are drugs for early Alzheimer’s called acetylcholinesterase inhibitors, which are very helpful in some people. They can increase the time people are independent for, which is really important. Unfortunately they don’t change the overall outcome of the disease and some people can experience side effects, such as minor dreams, hallucinations, or nausea – we always do a trial period before starting longer-term treatment.

Getting a diagnosis is vital in giving people the right treatment. It’s usually older people who get Alzheimer’s and they often have other health issues, so it’s important that everyone is aware there’s a memory issue. Often, someone will have been going to, for example, a heart clinic for years and no one realises they might have dementia – if they’ve not been taking their medications properly their heart disease then gets worse. That’s what my job as a geriatrician is about – thinking about the whole picture.

The biggest thing that makes a difference [to Alzheimer’s patients] is to understand what’s happening and find ways to cope with it in daily life…

What is the prognosis following early diagnosis?

This varies a lot and depends on other health issues a person may have; there’s no one size fits all. Some people can progress very slowly and really improve with drugs and support, whereas others may deteriorate much quicker.

Some research suggests modern drugs might be able to reverse Alzheimer’s. In the next 5-10 years, we’ll probably see more and more research into this; we need to know whether it’s safe.

A lot of your research involves studying twins in the TwinsUK cohort – what are you trying to find out?

Since my PhD I’ve been researching how learning and memory change as we get older – I’m interested in what might predict changes in cognition.

Right now I’m looking at how gut microbes might affect cognition. It’s possible that gut microbes may change the amount of inflammation in the body which could affect the brain and immune cells called microglia. If this happens, it might worsen dementia. This isn’t to say gut microbes might cause dementia on their own, but they could be part of the bigger picture of how it develops and progresses.

[Twins are] a very accessible way for people to understand the age-old dilemma of nature vs nurture.

How does studying twins help?

There are lots of benefits to studying twins. People really identify with why it’s useful to study twins – they’re a unique natural experiment. The public are also fascinated by identical genetics and it’s a very accessible way for people to understand the age-old dilemma of nature vs nurture.

Identical twins are brilliant for looking at the effect of the environment and lifestyle. We often check research results we find in all our twins using the identical twins. Identical twins are also great when we want to test something, like a dietary supplement. We can carry out much smaller scale studies in twins, as there is less genetic diversity.

For our twins, it’s an enjoyable way for them to take part in research as they come in to the department together – it’s a social thing.

What’s the most interesting thing you’ve found out about cognitive decline from studying twins?

The biggest thing I’ve found is that if you’re physically fitter you have much better cognitive change over time. We looked at changes in the twins over a ten-year period and found that your brain is much less likely to decline if you’re fitter. You may even be able to improve your cognition.

What do you think the long term impact of your research on cognitive ageing will be?

What we’re working towards at the moment is trying to understand what kind of changes people can make to their gut microbes that might improve inflammation and improve cognitive ageing. We have plans to study this, which would be very exciting.

The other thing is that it’s really important to get the message out to the public that keeping physically active is the best way to reduce cognitive ageing, the risk of Alzheimer’s and a whole range of other things. This is a really important message for those people who perhaps aren’t bothered so much by weight, but really care about their brain!

For more information about Alzheimer’s disease, and how to access support, take a look at the Alzheimer’s Society’s website.

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