̽��ֱ�� of Cambridge - Adam Butterworth

Scientists create ‘genetic atlas’ of proteins in human blood

cjb250 — Wed, 06 Jun 2018 17:00:44 +0000

̽��ֱ��study, published today in the journal Nature, characterised the genetic underpinnings of the human plasma ‘proteome’, identifying nearly 2,000 genetic associations with almost 1,500 proteins. Previously, there was only a small fraction of this knowledge, mainly because researchers could measure only a few blood proteins simultaneously in a robust manner.

̽��ֱ��researchers used a new technology (“SOMAscan”) developed by a company, SomaLogic, to measure 3,600 proteins in the blood of 3,300 people. They then analysed the DNA of these individuals to see which regions of their genomes were associated with protein levels, yielding a four-fold increase on previous knowledge.

“Compared to genes, proteins have been relatively understudied in human blood, even though they are the ‘effectors’ of human biology, are disrupted in many diseases, and are the targets of most medicines,” says Dr Adam Butterworth from the Department of Public Health and Primary Care at the ̽��ֱ�� of Cambridge, a senior author of the study. “Novel technologies are now allowing us to start addressing this gap in our knowledge.”

One of the uses for this genetic map is to identify particular biological pathways that cause disease, exemplified in the paper by pinpointing specific pathways that lead to Crohn’s disease and eczema.

“Thanks to the genomics revolution over the past decade, we’ve been good at finding statistical associations between the genome and disease, but the difficulty has been then identifying the disease-causing genes and pathways,” says Dr James Peters, one of the study’s principal authors. “Now, by combining our database with what we know about associations between genetic variants and disease, we are able to say a lot more about the biology of disease.”

In some cases, the researchers identified multiple genetic variants influencing levels of a protein. By combining these variants into a ‘score’ for that protein, they were able to identify new associations between proteins and disease. For example, MMP12, a protein previously associated with lung disease was found to be also related to heart disease – however, whereas higher levels of MMP12 are associated with lower risk of lung disease, the opposite is true in heart disease and stroke; this could be important as drugs developed to target this protein for treating lung disease patients could inadvertently increase the risk of heart disease.

MSD scientists were instrumental in highlighting how the proteomic genetic data could be used for drug discovery. For example, in addition to highlighting potential side-effects, findings of the study can further aid drug development through novel insights on protein targets of new and existing drugs. By linking drugs, proteins, genetic variation and diseases, the team has suggested existing drugs that could potentially also be used to treat a different disease, and increased confidence that certain drugs currently in development might be successful in clinical trials.

̽��ֱ��researchers are making all of their results openly available for the global community to use.

“Our database is really just a starting point,” says first author Benjamin Sun, also from the Department of Public Health and Primary Care. “We’ve given some examples in this study of how it might be used, but now it’s over to the research community to begin using it and finding new applications.”

Caroline Fox MD, Vice President and Head of Genetics and Pharmacogenomics at MSD, adds: “We are so pleased to participate in this collaboration, as it is a great example of how a public private partnership can be leveraged for research use in the broader scientific community.”

̽��ֱ��research was funded by MSD*, National Institute for Health Research, NHS Blood and Transplant, British Heart Foundation, Medical Research Council, UK Research and Innovation, and SomaLogic.

Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation, said: “Although our DNA provides our individual blueprint, it is the variations in the structure, function and amount of the proteins encoded by our genes which determine our susceptibility to disease and our response to medicines. This study provides exciting new insight into how proteins in the blood are controlled by our genetic make-up and opens up opportunities for developing new treatments for heart and circulatory disease.”

* MSD (trademark of Merck & Co., Inc., Kenilworth, NJ USA)

Reference
Sun, BB et al. Genomic atlas of the human plasma proteome. Nature; 7 June 2018; DOI: 10.1038/s41586-018-0175-2

An international team of researchers led by scientists at the ̽��ֱ�� of Cambridge and MSD has created the first detailed genetic map of human proteins, the key building blocks of biology. These discoveries promise to enhance our understanding of a wide range of diseases and aid development of new drugs.

Compared to genes, proteins have been relatively understudied in human blood, even though they are the ‘effectors’ of human biology, are disrupted in many diseases, and are the targets of most medicines

Adam Butterworth

qimono

Red blood cells

Researcher Profile: Benjamin Sun

“My work involves analysing big 'omic' data,” says Benjamin Sun, a clinical medical student on the MB-PhD programme at Cambridge. By this, he means data from genomic and proteomic studies, for example – terabytes of ‘big data’ that require the use of supercomputer clusters to analyse.

“My aim is to understand how variation in the human genome affects protein levels in blood, which I hope will allow us to better understand processes behind diseases and help inform drug targeting.”

Benjamin did pre-clinical training at Cambridge before intercalating – taking time out of his medical training to study a PhD, funded by an MRC-Sackler Scholarship, at the Department of Public Health and Primary Care.

“Having completed my PhD, I am currently spending the final two years of my programme at the Clinical School to complete my medical degree. My aim is to become an academic clinician like many of the inspiring figures here at the Cambridge. Balancing clinical work with research can sometimes be tough but definitely highly rewarding.”

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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A BLUEPRINT for blood cells: Cambridge researchers play leading role in major release of epigenetic studies

cjb250 — Thu, 17 Nov 2016 17:00:15 +0000

̽��ֱ��studies are part of BLUEPRINT, a large-scale research project bringing together 42 leading European universities, research institutes and industry entrepreneurs, with close to €30 million of funding from the EU. BLUEPRINT scientists have this week released a collection of 26 publications, part of a package of 41 publications being released by the International Human Epigenome Consortium.

One of the great mysteries in biology is how the many different cell types that make up our bodies are derived from a single stem cell and how information encoded in different parts of our genome are made available to be used by different cell types. Scientists have learned a lot from studying the human genome, but have only partially unveiled the processes underlying cell determination. ̽��ֱ��identity of each cell type is largely defined by an instructive layer of molecular annotations on top of the genome – the epigenome – which acts as a blueprint unique to each cell type and developmental stage.

Unlike the genome, the epigenome changes as cells develop and in response to changes in the environment. Defects in the proteins that read, write and erase the epigenetic information are involved in many diseases. ̽��ֱ��comprehensive analysis of the epigenomes of healthy and abnormal cells will facilitate new ways to diagnose and treat various diseases, and ultimately lead to improved health outcomes.

“This huge release of research papers will help transform our understanding of blood-related and autoimmune diseases,” says Professor Willem H Ouwehand from the Department of Haematology at the ̽��ֱ�� of Cambridge, one of the Principal Investigators of BLUEPRINT. “BLUEPRINT shows the power of collaboration among scientists across Europe in making a difference to our knowledge of how epigenetic changes impact on our health.”

Among the papers led by Cambridge researchers, Professor Nicole Soranzo and Dr Adam Butterworth have co-led a study analysing the effect of genetic variants in our DNA sequence on our blood cells. Using a genome-wide association analysis, the team identified more than 2,700 variants that affect blood cells, including hundreds of rare genetic variants that have far larger effects on the formation of blood cells than the common ones. Interestingly, they found genetic links between the effects of these variants and autoimmune diseases, schizophrenia and coronary heart disease, thereby providing new insights into the causes of these diseases.

A second study led by Professor Soranzo looked at the contribution of genetic and epigenetic factors to different immune cell characteristics in the largest cohort of this kind created with blood donors from the NHS Blood and Transplant centre in Cambridge.

Dr Mattia Frontini and Dr Chris Wallace, together with scientists at the Babraham Institute, have jointly led a third study mapping the regions of the genome that interact with genes in 17 different blood cell types. By creating an atlas of links between genes and the remote regions that regulate them in each cell type, they have been able to uncover thousands of genes affected by DNA modifications, pointing to their roles in diseases such as rheumatoid arthritis and other types of autoimmune disease.

Dr Frontini has also co-led a study with BLUEPRINT colleagues from the ̽��ֱ�� of Vienna that has developed a reference map of how epigenetic changes to DNA can program haematopoietic stem cells – a particular type of ‘master cell’ – to develop into the different types of blood and immune cells.

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, which helped fund the research, said: “Our genes are critical to our health and there’s still a wealth of information hidden in our genetic code. By taking advantage of a large scale international collaboration, involving the combined expertise of dozens of research groups, these unprecedented studies have uncovered potentially crucial knowledge for the development of new life saving treatments for heart disease and many other deadly conditions.

“Collaborations like this, which rely on funding from the public through charities and governments across the globe, are vital for analysing and understanding the secrets of our genetics. Research of this kind is helping us to beat disease and improve millions of lives.”

Departmental Affiliations

Professor Nicole Soranzo – Department of Haematology
Dr Adam Butterworth – Medical Research Council (MRC)/British Heart Foundation (BHF) Cardiovascular Epidemiology Unit
Dr Mattia Frontini – Department of Haematology, and Senior Research Fellow for the BHF Cambridge Centre for Research Excellence
Dr Chris Wallace – Department of Medicine and MRC Biostatistics Unit

References

Astle, WJ et al. ̽��ֱ��allelic landscape of human blood cell trait variation. Cell; 17 Nov 2016; DOI: 10.1016/j.cell.2016.10.042
Chen, L et al. Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell; 17 Nov 2016; DOI: 10.1371/journal.pbio.0000051
Javierre et al. Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters. Cell; 17 Nov 2016; DOI: 10.1016/j.cell.2016.09.037
Farlik et al. Cell Stem Cell; 17 Nov 2016; DOI: 10.1016/j.stem.2016.10.019

Cambridge researchers have played a leading role in several studies released today looking at how variation in and potentially heritable changes to our DNA, known as epigenetic modifications, affect blood and immune cells, and how this can lead to disease.

BLUEPRINT shows the power of collaboration among scientists across Europe in making a difference to our knowledge of how epigenetic changes impact on our health

Willem Ouwehand

haha_works

Detail of Epigenome

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‘Good’ cholesterol doesn’t always lower heart attack risk

cjb250 — Fri, 11 Mar 2016 09:48:43 +0000

̽��ֱ��discovery, published today in Science, could move researchers away from potentially ineffective HDL-raising drugs to treat coronary heart disease, and lead to the development of new treatments, helping to reduce their risk of heart attack.

̽��ֱ��researchers studied people with a rare genetic mutation in the SCARB1 gene, called the P376L variant, which causes the body to have high levels of ‘good’ HDL-C. High levels of ‘good’ cholesterol are commonly associated with reduced risk for coronary heart disease. Challenging this view, the researchers unexpectedly found that people with the rare mutation, who had increased levels of HDL-C, had an 80 per cent increased relative risk of the disease – a figure almost equivalent to the increased risk caused by smoking.

Coronary heart disease is responsible for nearly 70,000 deaths every year, almost entirely through heart attacks, making it the UK’s single biggest killer. ̽��ֱ��disease involves the build-up of fatty material, or plaque, in the coronary artery walls. If large quantities accumulate in the vessel walls, blood flow to the heart can become restricted or blocked, increasing risk of a heart attack.

̽��ֱ��international team of scientists included BHF-funded researchers Professor Sir Nilesh Samani at the ̽��ֱ�� of Leicester and Professor John Danesh at the ̽��ֱ�� of Cambridge. They initially looked at the DNA of 328 individuals with very high levels of HDL-C in the blood and compared them to 398 people with relatively low HDL-C. As the P376L variant they found was so rare, they then looked at its effects on HDL-C and heart disease in more than half a million additional people.

Dr Adam Butterworth, from the Cardiovascular Epidemiology Unit, ̽��ֱ�� of Cambridge, and co-investigator of this study, said: “We found that people carrying a rare genetic mutation causing higher levels of the so-called ‘good’ HDL-cholesterol are, unexpectedly, at greater risk of heart disease. This discovery could lead to new drugs that improve the processing of HDL-C to prevent devastating heart attacks.

“Large-scale collaborative research like this paves the way for further studies of rare mutations that might be significantly increasing people’s risk of a deadly heart attack. These discoveries also give researchers the knowledge we need to develop better treatments.”

Professor Peter Weissberg, Medical Director at the BHF, added said: “This is an important study that sheds light on one of the major puzzles relating to cholesterol and heart disease, which is that despite strong evidence showing HDL-C reduces heart disease risk, clinical trials on the effects of HDL-C-raising drugs have been disappointing.

“These new findings suggest that the way in which HDL-C is handled by the body is more important in determining risk of a heart attack than the levels of HDL-C in the blood. Only by understanding the underlying biology that links HDL-C with heart attacks can we develop new treatments to prevent them. These unexpected findings pave the way for further research into the SCARB1 pathway to identify new treatments to reduce heart attacks in the future.”

Additional funding for the study in the USA came from the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institute of Health.

Reference
Zanoni, P et al. Rare Variant in Scavenger Receptor BI raises HDL Cholesterol and Increases Risk of Coronary Heart Disease. Science; 10 Mar 2016; DOI: 10.1126/science.aad3517

Adapted from a press release from the British Heart Foundation

Some people with high levels of ‘good’ high density lipoprotein cholesterol (HDL-C) are at increased risk of coronary heart disease, contrary to earlier evidence that people with more HDL-C are usually at lower heart disease risk. This finding comes from an international study involving researchers at the ̽��ֱ�� of Cambridge, funded by the British Heart Foundation (BHF).

Large-scale collaborative research like this paves the way for further studies of rare mutations that might be significantly increasing people’s risk of a deadly heart attack

Adam Butterworth

geralt / Pixbay

Heart beat

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