̽��ֱ�� of Cambridge - gene

Many of us could carry up to 17kg of fat due to a change in a single gene

Anonymous — Thu, 27 May 2021 15:00:14 +0000

̽��ֱ��study led by scientists at the MRC Metabolic Diseases Unit which is part of the Wellcome-MRC Institute of Metabolic Science at the ̽��ֱ�� of Cambridge and the MRC Integrative Epidemiology Unit at the ̽��ֱ�� of Bristol is published today in Nature Medicine.

It has been known for a long time that obesity tends to run in families, but it was not until about 20 years ago that scientists started to discover that changes in specific genes can have very large effects on our weight even from early childhood.

One of these genes, the Melanocortin 4 Receptor (MC4R), makes a protein that is produced in the brain where it sends signals to our appetite centres, telling them how much fat we have stored. When the MC4R gene does not work properly, our brains think we have lower fat stores than we do, signalling that we are starving and need to eat.

̽��ֱ��research team found that around one in every 340 people may carry a disruptive mutation at MC4R. People who carry these mutations were more likely to have a greater weight from early childhood and, by 18 years of age, they were on average 17 kg (37 lbs or 2.5 stone) heavier, with the majority of this excess weight likely to be fat.

These results were found by studying the MC4R gene in a random sample of around 6,000 participants born in Bristol in 1990-91, who were recruited to Children of the 90s, a health study based at the ̽��ֱ�� of Bristol. This is a unique UK study that recruited approximately 80 percent of the births occurring in a specific region of the South West and which has continued to follow participants. As the Children of the 90s study managed to recruit such a high percentage of mothers during pregnancy, it is one of the most representative and comprehensive studies of its kind.

̽��ֱ��authors examined the MC4R gene in all 6,000 people and, whenever a mutation was found, went on to study its functional effects in the laboratory. This meticulous approach has provided the best estimates so far of the frequency and impact of MC4R mutations on people’s weight and body fat. Based on the frequency of mutations in this study, it is possible that around 200,000 people in the UK could carry a substantial amount of additional fat because of mutations in MC4R.

Professor Sir Stephen O’Rahilly, from the ̽��ֱ�� of Cambridge and one of the authors of the study, said: “Parents of obese children are often blamed for poor parenting and not all children obtain appropriate professional help. Our findings show that weight gain in childhood due to a single gene disorder is not uncommon. This should encourage a more compassionate and rational approach to overweight children and their families – including genetic analysis in all seriously obese children.”

Dr Kaitlin Wade, from the ̽��ֱ�� of Bristol’s MRC Integrated Epidemiology Unit and an author on the paper, added: “Work like this is really made possible as a result of the amazing properties presented by a study like Children of the 90s. Having biological samples for sequencing and rich life course data within a representative population sample is critical to allow new understanding and deep characterisation of important biological genetic effects like these.”

Professor Nic Timpson, Children of the 90s' Principal Investigator, and also one of the study’s authors, explained: “This work helps to recalibrate our understanding of the frequency and functional impact of rare MC4R mutations and will help to shape the future management of this important health factor – we extend our thanks to the participants of the Children of the 90s.”

Though the MC4R gene is a striking example, this is only one gene of many that affect our weight and there are likely to be further examples that emerge as genetic sequencing becomes more common.

In the longer term, knowledge of the brain pathways controlled by MC4R should help in the design of drugs that bypass the signalling blockade and help restore people to a healthy weight.

Reference
Wade KH et al. Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort. Nature Medicine; 27 May 2021

Adapted from a press release by the Wellcome-MRC Institute of Metabolic Science at the ̽��ֱ�� of Cambridge and the ̽��ֱ�� of Bristol

New research has found that one in every 340 people might carry a mutation in a single gene that makes them more likely to have a greater weight from early childhood and, by 18 years of age, they could be up to 30 pounds heavier with the excess weight likely to be mostly fat.

Our findings show that weight gain in childhood due to a single gene disorder is not uncommon. This should encourage a more compassionate and rational approach to overweight children and their families

Stephen O'Rahilly

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Weighing scales and tape measure

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Discovery of genetic variants that protect against obesity and type 2 diabetes could lead to new weight loss medicines

cjb250 — Thu, 18 Apr 2019 15:00:18 +0000

Scientists have known for several years that genes can influence a person’s weight. One of the genes that is known to play a key role in regulating weight is MC4R, which codes for the melanocortin 4 receptor. This receptor acts like a switch in the brain to suppress appetite. People who have genetic variants that disrupt this receptor gain weight easily.

Now, in a study published today in the journal Cell, researchers have shown that other genetic variants in the MC4R gene that increase the activity of this brain receptor can protect people from becoming overweight, a finding that could lead to the development of new medicines that ‘copy’ the protective effect of these genetic variants to achieve or maintain weight-loss.

A team led by Professors Sadaf Farooqi and Nick Wareham and Dr Claudia Langenberg at the Wellcome Trust-MRC Institute of Metabolic Science in Cambridge looked at the MC4R gene in half a million volunteers from the UK population who have taken part in the UK Biobank study, finding 61 distinct naturally-occurring genetic variants. While some of these genetic variants predisposed people to become obese, other variants provided protection against obesity and some of its major complications, such as type 2 diabetes and heart disease.

To investigate the reasons for this mystery, Professor Farooqi’s team, who previously showed that MC4R works in the brain as a ‘switch’ to tell us to stop eating after a meal, studied the function of these genetic variants in a number of laboratory experiments. They found that MC4R gene variants linked to higher obesity risk stopped the gene from working, whereas variants that offered protection against obesity kept the gene ‘switched on’.

Around six per cent of study participants carried genetic variants that caused the receptor to remain ‘switched on’. People with these variants would eat less, which could explain their lower weight. People with two copies of these particular variants (1 in over 1,000 people) were on average 2.5 kg lighter than people without the variants and had a 50% lower risk of type 2 diabetes and heart disease.

“This study drives home the fact that genetics plays a major role in why some people are obese – and that some people are fortunate enough to have genes that protect them from obesity,” says Professor Farooqi of the ̽��ֱ�� of Cambridge Metabolic Research Laboratories.

̽��ֱ��discovery adds to recent work by the team which showed that some slim people have a genetic advantage when it comes to maintaining their weight.

“It doesn’t mean that we can’t influence our weight by watching what we eat, but it does mean the odds are stacked against some people and in favour of others,” added Professor Farooqi.

When the researchers looked in detail at the genetic variants in laboratory experiments, they found that MC4R can send signals through a pathway – known as the beta-arrestin pathway – that had not previously been linked to weight regulation. Genetic variants that sent signals preferentially through this pathway were the ones driving the association with protection against obesity and its complications and, importantly, were also associated with lower blood pressure. Designing drugs that mimic the effect of the protective variants in MC4R could provide new, safer weight loss therapies.

“A powerful emerging concept is that genetic variants that protect against disease can be used as models for the development of medicines that are more effective and safer,” said Dr Luca Lotta, Senior Clinical Investigator at the Medical Research Council Epidemiology Unit and joint lead author of the study. “Our findings may pave the way for a new generation of weight loss therapies that activate MC4R preferentially via the beta-arrestin pathway.”

“Our work would not have been possible without the unique blend of expertise in large-scale genetic epidemiology analysis and laboratory experiments at the Institute of Metabolic Science,” says Professor Wareham, Director of the MRC Epidemiology Unit and Co-Director of the Institute.

“Genetic studies of thousands of people and a functional understanding of the mechanisms behind protective genetic variants can really help us inform the development of a new generation of medicines for common diseases like obesity and diabetes that affect millions of people globally.”

̽��ֱ��work was funded by the MRC and Wellcome, with support from the NIHR Cambridge Biomedical Research Centre.

Reference
Lotta, LA, Mokrosiński, J et al. Human gain-of-function MC4R variants show signaling bias and protect against obesity. Cell; 18 April 2019; DOI: 10.1016/j.cell.2019.03.044

Around four million people in the UK carry genetic variants that protect them from obesity, type 2 diabetes and heart disease, suggests new research from the ̽��ֱ�� of Cambridge. ̽��ֱ��team say the discovery could lead to the development of new drugs that help people lose weight.

This study drives home the fact that genetics plays a major role in why some people are obese – and that some people are fortunate enough to have genes that protect them from obesity

Sadaf Farooqi

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Mitochondrial diseases could be treated with gene therapy, study suggests

sc604 — Mon, 24 Sep 2018 15:00:00 +0000

̽��ֱ��researchers, led by the ̽��ֱ�� of Cambridge, applied an experimental gene therapy treatment in mice and were able to successfully target and eliminate the damaged DNA in mitochondria which causes the devastating conditions.

Their results, published in the journal Nature Medicine, could provide a practical route to treating patients with these diseases and may provide a future alternative to mitochondrial replacement therapy, or ‘three-parent IVF’. This is the first time programmable genome engineering tools have been used inside a living animal, resulting in such significant modification of mitochondrial DNA.

Mitochondria are the powerhouses inside our cells, producing energy and carrying their own DNA. They are inherited from a person’s mother via the egg, but if they are damaged, it can result in a serious mitochondrial disease. For example, MELAS Syndrome is a severe multi-system disorder causing progressive loss of mental and movement abilities, which usually becomes apparent in early childhood.

There are typically about 1000 copies of mitochondrial DNA per cell, and the percentage of these that are damaged, or mutated, will determine whether a person will suffer from mitochondrial disease or not. Usually, more than 60% of the mitochondrial DNA molecules in a cell need to be mutated for the disease to emerge, and the more mutated mitochondrial DNA a person has, the more severe their disease will be. Conversely, if the percentage of mutated DNA can be reduced, the disease could potentially be treated.

Mitochondrial diseases are currently incurable, although a new IVF technique of mitochondrial transfer gives families affected by mitochondrial disease the chance of having healthy children – removing affected mitochondria from an egg or embryo and replacing them with healthy ones from a donor.

“Mitochondrial replacement therapy is a promising approach to prevent transmission of mitochondrial diseases, however, as the vast majority of mitochondrial diseases have no family history, this approach might not actually reduce the proportion of mitochondrial disease in the population,” said Dr Payam Gammage, a postdoctoral researcher in the MRC Mitochondrial Biology Unit, and the paper’s first author.

“One idea for treating these devastating diseases is to reduce the amount of mutated mitochondrial DNA by selectively destroying the mutated DNA, and allowing healthy DNA to take its place,” said Dr Michal Minczuk, also from the Medical Research Council (MRC) Mitochondrial Biology Unit, and the study’s senior author.

To test an experimental gene therapy treatment, which has so far only been tested in human cells grown in petri dishes in a lab, the researchers used a mouse model of mitochondrial disease that has the same mutation as some human patients.

̽��ֱ��gene therapy treatment, known as the mitochondrially targeted zinc finger-nuclease, or mtZFN, recognises and then eliminates the mutant mitochondrial DNA, based on the DNA sequence differences between healthy and mutant mitochondrial DNA. As cells generally maintain a stable number of mitochondrial DNA copies, the mutated copies that are eliminated are replaced with healthy copies, leading to a decrease in the mitochondrial mutation burden that results in improved mitochondrial function.

̽��ֱ��treatment was delivered into the bloodstream of the mouse using a modified virus, which is then mostly taken up by heart cells. ̽��ֱ��researchers found that the treatment specifically eliminates the mutated mitochondrial DNA, and resulted in measures of heart metabolism improving.

Following on from these results, the researchers hope to take this gene therapy approach through clinical trials, in the hope of producing an effective treatment for mitochondrial diseases.

This work was supported by the Medical Research Council and was performed in collaboration with Sangamo Therapeutics and the Max Planck Institute for Biology of Ageing in Cologne.

Reference:
Payam A. Gammage et al. ‘Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo.’ Nature Medicine (2018). DOI: 10.1038/s41591-018-0165-9.

Researchers have developed a genome-editing tool for the potential treatment of mitochondrial diseases: serious and often fatal conditions which affect 1 in 5,000 people.

One idea for treating these devastating diseases is to reduce the amount of mutated mitochondrial DNA by selectively destroying the mutated DNA, and allowing healthy DNA to take its place.

Michal Minczuk

NICHD/U

Mitochondria

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Major study of genetics of breast cancer provides clues to mechanisms behind the disease

cjb250 — Mon, 23 Oct 2017 15:39:07 +0000

Of these variants, reported today in the journals Nature and Nature Genetics, 65 are common variants that predispose to breast cancer and a further seven predispose specifically to oestrogen-receptor negative breast cancer – the subset of cases that do not respond to hormonal therapies, such as the drug tamoxifen.

Breast cancer is caused by complex interactions between a large number of genetic variants and our environment. ̽��ֱ��inherited component of breast cancer risk is due to a combination of rare variants in genes such as BRCA1 and BRCA2 that confer a high risk of the disease, and many commoner genetic variants that each confer only a small risk. ̽��ֱ��newly identified risk regions nearly double the number that are already known, thereby bringing the number of known common variants associated with breast cancer to around 180.

̽��ֱ��findings are the result of work by the OncoArray Consortium, a huge endeavour involving 550 researchers from around 300 different institutions in six continents. In total, they analysed genetic data from 275,000 women, of whom 146,000 had been diagnosed with breast cancer.

Professor Doug Easton from the Centre for Cancer Genetic Epidemiology and a Fellow at Homerton College, the ̽��ֱ�� of Cambridge, one of the lead investigators on the study, says: “These findings add significantly to our understanding of the inherited basis of breast cancer. As well as identifying new genetic variants, we have also confirmed many that we had previously suspected. There are some clear patterns in the genetic variants that should help us understand why some women are predisposed to breast cancer, and which genes and mechanisms are involved.”

By combining epidemiological data with other data from breast tissue, the researchers were able to make plausible predictions of the target genes in the large majority of cases. In addition, they showed for the first time that these genes are often the same as those that are altered in breast tumours – when a tumour develops, the DNA within the cancer cells themselves mutates.

Most of the variants found by OncoArray were not found within genes, but rather within regions of the genome that regulate the activity of nearby genes. When the researchers looked at the pattern of these genetic regions, they discovered that this differed from that of those regions involved in predisposition to other common diseases.

Professor Peter Kraft at Harvard TH Chan School of Public Health, USA, says: “Given the size of these studies, we expected that we would find a lot of new breast cancer risk variants, but the studies tells us a lot more about which genes are involved, revealing many previously unsuspected genes and genetic mechanisms underlying breast carcinogenesis. This should provide guidance for a lot of future research.”

Around 70% of all cases of breast cancer are oestrogen-receptor positive, meaning that the cancer cells have a particular protein (known as a receptor) that responds to the female sex hormone oestrogen, enabling the tumour to grow. However, not all cancer cells carry this receptor – these are known as oestrogen-receptor negative. ̽��ֱ��studies identified genetic regions specifically associated with either oestrogen-receptor positive or oestrogen receptor negative breast cancer, underscoring the fact that these are biologically distinct cancers that develop differently.

“These findings may inform improved risk prediction, both for the general population and BRCA1 mutation carriers,” says Associate Professor Roger Milne at Cancer Council Victoria in Melbourne. “A better understanding of the biological basis of oestrogen receptor negative breast cancer may lead to more effective preventive interventions and treatments.”

̽��ֱ��risk variants identified in the two studies are common: while some are carried by one woman in a hundred, others are carried by more half of all women. Individually, the risks conferred by each variant are modest; however, because they are common and their effects multiply together, the combined effect is considerable. For example, the researchers estimated that one percent of women have a risk of breast cancer that is more than 3 times greater than the population at large. Larger differences in risk can be found if the genetic variants are combined with other hormonal and lifestyle factors that influence breast cancer risk.

̽��ֱ��researchers believe these differences may be sufficient to change practice, such as in how women at different risks are screened. In many countries, women are offered screening by mammography from age 50; women at increased risk because of a family history can be offered screening earlier, and those at particularly high risk can be offered screening by MRI, which is more sensitive.

“Using data from genomic studies, combined with information on other known risk factors, will allow better breast cancer risk assessment, therefore helping to identify a small but meaningful proportion of women at high risk of breast cancer,” says Professor Jacques Simard at Université Laval, Quebec city, Canada.

“These women may benefit from more intensive screening, starting at a younger age, or using more sensitive screening techniques, allowing early detection and prevention of the disease. At the same time, this personalised information will also be useful to adapt screening modalities for women at substantially lower risk.”

Professor Karen Vousden, Cancer Research UK’s chief scientist, said: “This study is a great example of how international collaboration can help improve the understanding of cancer. ̽��ֱ��results, gathered from around the world, help pinpoint the genetic changes linked to a women’s risk of breast cancer. Learning which women are at higher risk of breast cancer could help identify who may benefit from earlier screening, and spare women at a lower risk from having to attend screening if it’s unlikely to benefit them.”

Reference
Michailidou, K et al. Association analysis identifies 65 new breast cancer risk loci. Nature; 23 Oct 2017; DOI: 10.1038/nature24284

Milne, RL et al. Identification of ten variants associated with risk of estrogen receptor negative breast cancer. Nature Genetics; 23 Oct 2017; DOI: 10.1038/ng.3785

Funding
Genotyping of the OncoArray was principally funded from three sources: the Personalised Risk Stratification for Early Detection and Prevention of Breast Cancer (PERSPECTIVE) project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie, de la Science et de l’Innovation du Québec’ through Genome Québec, and the Quebec Breast Cancer Foundation; the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project; and Cancer Research UK. BCAC is funded by Cancer Research UK and the European Union Horizon 2020 programme (BRIDGES and B-CAST).

Seventy-two new genetic variants that contribute to the risk of developing breast cancer have been identified by a major international collaboration involving hundreds of researchers worldwide.

There are some clear patterns in the genetic variants that should help us understand why some women are predisposed to breast cancer, and which genes and mechanisms are involved

Doug Easton

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Quadruple helix form of DNA may aid in the development of targeted cancer therapies

sc604 — Mon, 12 Sep 2016 15:00:01 +0000

Scientists have identified where a four-stranded version of DNA exists within the genome of human cells, and suggest that it may hold a key to developing new, targeted therapies for cancer.

In work funded by Cancer Research UK and EMBO, the researchers, from the ̽��ֱ�� of Cambridge, found that these quadruple helix structures occur in the regions of DNA that control genes, particularly cancer genes, suggesting that they may play a role in switching genes on or off. ̽��ֱ��results, reported in the journal Nature Genetics, could also have implications for cancer diagnostics and the development of new targeted treatments.

Most of us are familiar with the double helix structure of DNA, but there is also a version of the molecule which has a quadruple helix structure. These structures are often referred to as G-quadruplexes, as they form in the regions of DNA that are rich in the building block guanine, usually abbreviated to ‘G’. These structures were first found to exist in human cells by the same team behind the current research, but at the time it was not exactly clear where these structures were found in the genome, and what their role was, although it was suspected that they had a link with certain cancer genes.

“There have been a number of different connections made between these structures and cancer, but these have been largely hypothetical,” said Professor Shankar Balasubramanian, from Cambridge’s Department of Chemistry and Cancer Research UK Cambridge Institute, and the paper’s senior author. “But what we’ve found is that even in non-cancer cells, these structures seem to come and go in a way that’s linked to genes being switched on or off.”

Starting with a pre-cancerous human cell line, the researchers used small molecules to change the state of the cells in order to observe where the G-quadruplexes might appear. They detected approximately 10,000 G-quadruplexes, primarily in regions of DNA associated with switching genes on or off, and particularly in genes associated with cancer.

“What we observed is that the presence of G-quadruplexes goes hand in hand with the output of the associated gene,” said Balasubramanian. This suggests that G-quadruplexes may play a similar role to epigenetic marks: small chemical modifications which affect how the DNA sequence is interpreted and control how certain genes are switched on or off.

̽��ֱ��results also suggest that G-quadruplexes hold potential as a molecular target for early cancer diagnosis and treatment, in particular for so-called small molecule treatments which target cancer cells, instead of traditional treatments which hit all cells.

“We’ve been looking for an explanation for why it is that certain cancer cells are more sensitive to small molecules that target G-quadruplexes than non-cancer cells,” said Balasubramanian. “One simple reason could be that there are more of these G-quadruplex structures in pre-cancerous or cancer cells, so there are more targets for small molecules, and so the cancer cells tend to be more sensitive to this sort of intervention than non-cancer cells.

“It all points in a certain direction, and suggests that there’s a rationale for the selective targeting of cancer cells.”

“We found that G-quadruplexes appear in regions of the genome where proteins such as transcription factors control cell fate and function,” said Dr Robert Hänsel-Hertsch, the paper’s lead author. “ ̽��ֱ��finding that these structures may help regulate the way that information is encoded and decoded in the genome will change the way we think this process works.”

Dr Emma Smith, Cancer Research UK’s science information manager, said: “Figuring out the fundamental processes that cancer cells use to switch genes on and off could help scientists develop new treatments that work against many types of the disease. And exploiting weaknesses in cancer cells could mean this approach would cause less damage to healthy cells, reducing potential side effects. It’s still early days, but promising leads like this are where the treatments of the future will come from.”

Reference:
Robert Hänsel-Hertsch et. al. ‘G-quadruplex structures mark human regulatory chromatin.’ Nature Genetics (2016). DOI: 10.1038/ng.3662

Researchers have identified the role that a four-stranded version of DNA may play in the role of cancer progression, and suggest that it may be used to develop new targeted cancer therapies.

It all points in a certain direction, and suggests that there’s a rationale for the selective targeting of cancer cells.

Shankar Balasubramanian

Thomas Splettstoesser

Crystal structure of parallel quadruplexes from human telomeric DNA.

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Major global study reveals new hypertension and blood pressure genes

sc604 — Mon, 12 Sep 2016 15:00:00 +0000

̽��ֱ��discoveries include DNA changes in three genes that have much larger effects on blood pressure in the population than previously seen, providing new insights into the physiology of hypertension and suggesting new targets for treatment.

High blood pressure or hypertension is a major risk factor for cardiovascular disease and premature death. It is estimated to be responsible for a larger proportion of global disease burden and premature mortality than any other disease risk factor. However, there is limited knowledge on the genetics of blood pressure.

̽��ֱ��teams investigated the genotypes of around 347,000 people and their health records to find links between their genetic make-up and cardiovascular health. ̽��ֱ��participants included healthy individuals and those with diabetes, coronary artery disease and hypertension, from across Europe, (including the UK, Denmark, Sweden, Norway, Finland and Estonia), the USA, Pakistan and Bangladesh. ̽��ֱ��study brought together around 200 investigators from across 15 countries.

Study author Professor Patricia Munroe from QMUL said: “We already know from earlier studies that high blood pressure is a major risk factor for cardiovascular disease. Finding more genetic regions associated with the condition allows us to map and understand new biological pathways through which the disease develops, and also highlight potential new therapeutic targets. This could even reveal drugs that are already out there but may now potentially be used to treat hypertension.”

Most genetic blood pressure discoveries until now have been of common genetic variants that have small effects on blood pressure. ̽��ֱ��study, published in Nature Genetics, has found variants in three genes that appear to be rare in the population, but have up to twice the effect on blood pressure.

“ ̽��ֱ��sheer scale of our study has enabled us to identify genetic variants carried by less than one in a hundred people that affect blood pressure regulation,” said study author, Dr Joanna Howson from Cambridge’s Department of Public Health and Primary Care. “While we have known for a long time that blood pressure is a risk factor for coronary heart disease and stroke, our study has shown that there are common genetic risk factors underlying these conditions.”

RBM47 is a gene that encodes for a protein responsible for modifying RNA. RRAS is involved in cell cycle processes and has already been implicated in a syndrome related to ‘Noonan syndrome’ which is characterised by heart abnormalities. COL21A1 is involved in collagen formation in many tissues, including the heart and aorta. COL21A1 and RRAS warrant particular interest since both are involved in blood vessel remodelling, with relevance to hypertension.

̽��ֱ��team also found a mutation in a key molecule ENPEP that affects blood pressure. This gene codes for an enzyme that is a key molecule involved in regulating blood pressure through the dilation and constriction of blood vessels, and is currently a therapeutic target.

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation which part-funded the research, said: “Large scale genetic studies continue to expand the number of genes that may contribute to the development of heart disease, or risk factors such as high blood pressure. But so far most of the genes discovered in these studies individually have only very small effects on risk – though they may still provide valuable clues for new drug targets.

“This study has increased the number of genes implicated in control of blood pressure to almost 100 and, in the process, has also identified three genes that have larger effects on blood pressure than previously found.”

̽��ֱ��study was also funded by the National Institute for Health Research (NIHR), National Institute of Health (NIH), Wellcome Trust and the Medical Research Council.

Reference:
Surendran et al. ‘Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension’. Nature Genetics 2016. DOI: 10.1038/ng.3654

Thirty-one new gene regions linked with blood pressure have been identified in one of the largest genetic studies of blood pressure to date, involving over 347,000 people, and jointly led by Queen Mary ̽��ֱ�� of London (QMUL) and the ̽��ֱ�� of Cambridge.

While we have known for a long time that blood pressure is a risk factor for coronary heart disease and stroke, our study has shown that there are common genetic risk factors underlying these conditions.

Joanna Howson

Yale Rosen

Pulmonary hypertension-associated vasculitis

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Gene signature in healthy brains pinpoints the origins of Alzheimer’s disease

sc604 — Wed, 10 Aug 2016 18:00:00 +0000

Researchers have discovered a gene signature in healthy brains that echoes the pattern in which Alzheimer’s disease spreads through the brain much later in life. ̽��ֱ��findings, published in the journal Science Advances, could help uncover the molecular origins of this devastating disease, and may be used to develop preventative treatments for at-risk individuals to be taken well before symptoms appear.

̽��ֱ��results, by researchers from the ̽��ֱ�� of Cambridge, identified a specific signature of a group of genes in the regions of the brain which are most vulnerable to Alzheimer’s disease. They found that these parts of the brain are vulnerable because the body’s defence mechanisms against the proteins partly responsible for Alzheimer’s disease are weaker in these areas.

Healthy individuals with this specific gene signature are highly likely to develop Alzheimer’s disease in later life, and would most benefit from preventative treatments, if and when they are developed for human use.

Alzheimer’s disease, the most common form of dementia, is characterised by the progressive degeneration of the brain. Not only is the disease currently incurable, but its molecular origins are still unknown. Degeneration in Alzheimer’s disease follows a characteristic pattern: starting from the entorhinal region and spreading out to all neocortical areas. What researchers have long wondered is why certain parts of the brain are more vulnerable to Alzheimer’s disease than others.

“To answer this question, what we’ve tried to do is to predict disease progression starting from healthy brains,” said senior author Professor Michele Vendruscolo of the Centre for Misfolding Diseases at Cambridge’s Department of Chemistry. “If we can predict where and when neuronal damage will occur, then we will understand why certain brain tissues are vulnerable, and get a glimpse at the molecular origins of Alzheimer’s disease.”

One of the hallmarks of Alzheimer’s disease is the build-up of protein deposits, known as plaques and tangles, in the brains of affected individuals. These deposits, which accumulate when naturally-occurring proteins in the body fold into the wrong shape and stick together, are formed primarily of two proteins: amyloid-beta and tau.

“We wanted to know whether there is something special about the way these proteins behave in vulnerable brain tissue in young individuals, long before the typical age of onset of the disease,” said Vendruscolo.

Vendruscolo and his colleagues found that part of the answer lay within the mechanism of control of amyloid-beta and tau. Through the analysis of more than 500 samples of healthy brain tissues from the Allen Brain Atlas, they identified a signature of a group of genes in healthy brains. When compared with tissue from Alzheimer’s patients, the researchers found that this same pattern is repeated in the way the disease spreads in the brain.

“Vulnerability to Alzheimer’s disease isn’t dictated by abnormal levels of the aggregation-prone proteins that form the characteristic deposits in disease, but rather by the weaker control of these proteins in the specific brain tissues that first succumb to the disease,” said Vendruscolo.

Our body has a number of effective defence mechanisms which protect it against protein aggregation, but as we age, these defences get weaker, which is why Alzheimer’s generally occurs in later life. As these defence mechanisms, collectively known as protein homeostasis systems, get progressively impaired with age, proteins are able to form more and more aggregates, starting from the tissues where protein homeostasis is not so strong in the first place.

Earlier this year, the same researchers behind the current study identified a possible ‘neurostatin’ that could be taken by healthy individuals in order to slow or stop the progression of Alzheimer’s disease, in a similar way to how statins are taken to prevent heart disease. ̽��ֱ��current results suggest a way to exploit the gene signature to identify those individuals most at risk and who would most benefit from taking a neurostatin in earlier life.

Although a neurostatin for human use is still quite some time away, a shorter-term benefit of these results may be the development of more effective animal models for the study of Alzheimer’s disease. Since the molecular origins of the disease have been unknown to date, it has been difficult to breed genetically modified mice or other animals that repeat the full pathology of Alzheimer’s disease, which is the most common way for scientists to understand this or any disease in order to develop new treatments.

“It is exciting to consider that the molecular origins identified here for Alzheimer’s may predict vulnerability for other diseases associated with aberrant aggregation – such as ALS, Parkinson’s and frontotemporal dementia,” said Rosie Freer, a PhD student in the Department of Chemistry and the study’s lead author. “I hope that these results will help drug discovery efforts – that by illuminating the origin of disease vulnerability, there will be a clearer target for those working to cure Alzheimer’s.”

“ ̽��ֱ��results of this particular study provide a clear link between the key factors that we have identified as underlying the aggregation phenomenon and the order in which the effects of Alzheimer’s disease are known to spread through the different regions of the brain,” said study co-author Professor Christopher Dobson, who is Master of St John’s College, Cambridge. “Linking the properties of specific protein molecules to the onset and spread of neuronal damage is a crucial step in the quest to find effective drugs to combat this dreadful neurodegenerative condition, and potentially other diseases related to protein misfolding and aggregation.”

Addressing these problems represents the core programme of research of the Centre for Misfolding Diseases, which is directed by Chris Dobson, Tuomas Knowles and Michele Vendruscolo. ̽��ֱ��primary mission of the Centre is to develop a fundamental understanding of the molecular origins of the variety of disorders associated with the misfolding and aggregation of proteins, which include Parkinson's disease, ALS and type II diabetes as well as Alzheimer's disease, and then to use such understanding for the rational design of novel therapeutic strategies.

Reference:
R. Freer et. al. ‘A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer’s disease.’ Science Advances (2016). DOI: 10.1126/sciadv.1600947

A specific gene expression pattern maps out which parts of the brain are most vulnerable to Alzheimer’s disease, decades before symptoms appear, and helps define the molecular origins of the disease.

We wanted to know whether there is something special about the way these proteins behave in vulnerable brain tissue in young individuals, long before the typical age of onset of the disease.

Michele Vendruscolo

J. Freer

In healthy tissues, a gene expression signature associated with amyloid-beta and tau aggregation echoes the progression of AD well before the onset of the disease.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Study provides clues to why some breast cancers are hard to beat

cjb250 — Tue, 10 May 2016 09:50:53 +0000

Researchers from the Cancer Research UK Cambridge Institute at the ̽��ֱ�� of Cambridge analysed tumour samples from the METABRIC study – which revealed breast cancer can be classified as ten different diseases – to get a deeper understanding of the genetic faults of these ten subtypes.

They found 40 mutated genes that cause breast cancer to progress. Only a fraction of these genes were previously known to be involved in breast cancer development. They also discovered that one of the more commonly mutated genes, called PIK3CA, is linked to lower chances of survival for three of the ten breast cancer subgroups. Crucially, this might help explain why drugs targeting PIK3CA work for some women but not for others.

̽��ֱ��researchers believe the results could in the future help find drugs to target these genetic faults, stopping the disease from progressing. ̽��ֱ��research could also provide vital information to help design breast cancer trials and improved tests for the disease.

̽��ֱ��findings add a more detailed layer of information to METABRIC, a major study involving 2,000 patients. METABRIC was the largest molecular profiling study looking at how patients progress after treatment for any type of cancer. It was carried out by Cancer Research UK, in collaboration with the British Columbia Cancer Agency.

Professor Carlos Caldas, lead author at the ̽��ֱ�� of Cambridge, said: “ ̽��ֱ��METABRIC study mapped out the genetic blueprints for breast cancer. And these new results give us even more detail about which genetic faults could be linked to how different types of breast cancer develop and progress.

“ ̽��ֱ��information could in the future help design clinical trials for breast cancer patients, or give researchers more flags to look out for in liquid biopsies, a type of test used to detect genetic material in the blood that is released by dying cancer cells.”

̽��ֱ��results will be made available to the public so that other researchers can benefit from the work.

Professor Peter Johnson, Cancer Research UK’s chief clinician, said: “Our research continues to highlight just how complicated cancers are, but we are managing to solve these puzzles faster than ever. This study gives us more vital information about how breast cancer develops and why some types are more difficult to treat than others, and this information is a great resource for researchers all over the world. Research like this will help us invent new diagnostic tests to guide treatment for breast cancer patients in the future.”

Reference
Pereira et al., ̽��ֱ��somatic mutation profile of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nature Communications; 10 May 2016. DOI: 10.1038/ncomms11479

Adapted from a press release from Cancer Reserch UK.

Scientists have unearthed crucial new genetic information about how breast cancer develops and the genetic changes which can be linked to survival, according to a study published in Nature Communications today.

These new results give us even more detail about which genetic faults could be linked to how different types of breast cancer develop and progress

Carlos Caldas

Adriënne

solidarity against cancer

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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