Public Release: 

Landmark project shows heart disease and arthritis risk raised by genetic changes in blood

As part of the BLUEPRINT project, scientists have discovered how variation in blood cell characteristics and numbers affects the risk of complex diseases such as heart disease and autoimmune diseases including rheumatoid arthritis and type 1 diabetes

Wellcome Trust Sanger Institute

Today in Cell and associated journals, 24 research studies from the landmark BLUEPRINT project and IHEC consortia reveal how variation in blood cells' characteristics and numbers can affect a person's risk of developing complex diseases such as heart disease, and autoimmune diseases including rheumatoid arthritis, asthma, coeliac disease and type 1 diabetes.

The papers, along with another 17 in other high-impact journals, are the culmination of a five-year, £25 million (€30 million) project that brought together 42 leading European universities, research institutes and industry partners. The project's goals were to explore and describe the range of epigenetic changes that take place in bone marrow as stem cells develop into different types of mature blood cell. It also sought to match epigenetic changes and genetic differences to the physical characteristics of each cell type and use this knowledge to understand how these can lead to blood disorders, cancer and other complex diseases*.

As part of BLUEPRINT, Wellcome Trust Sanger Institute led two of the six papers being published in the journal Cell today.

In the first study, Sanger Institute researchers worked closely with colleagues at the University of Cambridge and the University of Oxford to carry out the largest and most in-depth study of DNA and blood cell characteristics using the UK BioBank resource and the INTERVAL study**. By comparing almost 30 million DNA sequence differences in more than 173,000 people with variation in the physical properties of blood cells the scientists identified 2,500 previously undiscovered locations in the genome that influence blood cell characteristics and functions. Further work showed that genetic differences affecting some of these characteristics are linked to increased risk of heart attack, or to rheumatoid arthritis and other common autoimmune diseases.

Dr William Astle, from the University of Cambridge said: "The scale, resolution and homogeneity of our work were vital. Because we examined so many people we were able to discover important 'rare and low frequency' genetic differences that are present in fewer than 10 per cent of the population. We found that these can have a much larger impact on the characteristics of blood cells than the common differences studied previously. Of the more than 300 rare and low frequency difference we found, 74 appear to affect the structure of proteins. These give us important clues as to which biological pathways are involved in controlling the production, function and characteristics of blood cells."

The team found that genetic differences that cause people to have more young red blood cells in their peripheral bloodstreams also increase the risk they will have a heart attack.

Dr Adam Butterworth, one of the study's senior authors, from the University of Cambridge said: "When mature red blood cells rupture in our blood the body replaces them with new, young red cells - a process known as haemolysis. So we think that increased haemolysis and increased risk of coronary heart disease are affected by the same biological pathways. Identifying these pathways may offer new treatment possibilities."

In another new finding, the research team showed that genetic differences that increased the amount of certain white blood cells, known as eosinophils, also increased the risk of a person developing rheumatoid arthritis, asthma, coeliac disease and type 1 diabetes.

In the second Cell paper, researchers collaborated with scientists at the University of Cambridge, McGill University in Canada and several UK and European institutions to explore the role that epigenetics plays in the development and function of three major human immune cell types: CD14+ monocytes, CD16+ neutrophils and naïve CD4+ T cells, from the genomes of 197 individuals. They studied the contributions of various genetic control mechanisms, including epigenetic changes such as methyl tags on promoter regions in the DNA and histone modifications, to understand how these different levels of regulation interacted with genetic differences to change the expression of genes, immune function and, ultimately, human disease.

The team identified 345 regions of the genome where they could pinpoint the likely molecular causes underlying a person's predisposition to immune-related diseases such as inflammatory bowel disease, type 1 diabetes and multiple sclerosis.

Dr Tomi Pastinen, senior author on the second study, from McGill University said: "We have created an expansive, high-resolution atlas of variations that deepens our understanding of the interplay between the genetic and epigenetic machinery that drives the three primary cells of the human immune system. We have identified hundreds of genetic variations associated with autoimmune diseases that appear to affect the activity of genes in specific regions of the genome, pointing to biological pathways that may be involved in disease and which, ultimately, may be treatable with medication."

Professor Nicole Soranzo, senior author on both studies from the Sanger Institute and University of Cambridge, added: "The BLUEPRINT project has provided the worldwide research community with detailed insights and understandings that will form the basis of important blood cell research for many years to come. When integrated with large-scale genetic studies, these results and data inform understanding of how differences in the human genome and epigenome interact to cause devastating common diseases, and inform new avenues for treating these conditions."

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Notes to Editors

Publications

1. Astle WJ et al. (2016) The allelic landscape of human blood cell trait variation and links to common complex disease. Cell http://dx.doi.org/10.1016/j.cell.2016.10.042

2. Chen L et al. (2016) Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell http://dx.doi.org/10.1371/journal.pbio.0000051

*About BLUEPRINT

One of the great mysteries in biology is how the many different cell types that make up our bodies are derived from a single cell and from one DNA sequence, or genome. We have learned a lot from studying the human genome, but have only partially unveiled the processes underlying cell determination. The 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 factors that read, write and erase the epigenetic blueprint are involved in many diseases. The 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.

A collection of 42 coordinated papers now published by scientists from across the International Human Epigenome Consortium (IHEC) sheds light on these processes, taking global research in the field of epigenomics a major step forward. A set of 24 manuscripts has been released as a package in Cell and Cell Press-associated journals, and an additional 17 papers have been published in other high-impact journals. These papers represent the most recent work of IHEC member projects from Canada, the European Union, Germany, Japan, Singapore, South Korea, and the United States. The collection of publications showcases the achievements and scientific progress made by IHEC in core areas of current epigenetic investigations.

** For more information visit: http://www.intervalstudy.org.uk/

Participating Centres

For a full list of all 42 participating centres participating in BLUEPRINT, please see: http://www.blueprint-epigenome.eu/index.cfm?p=7D26EAFE-B366-DE94-6717271B880916E2

Selected Websites

BLUEPRINT

BLUEPRINT is a large-scale research project receiving close to 30 million euro funding from the EU and involving 41 leading European universities, research institutes and industry entrepreneurs. The BLUEPRINT project aims to further the understanding of how our genes are activated or repressed in both healthy and diseased human cells. It aims to generate at least 100 reference epigenomes and study them to advance and exploit knowledge of the underlying biological processes and mechanisms in health and disease. http://www.blueprint-epigenome.eu/

IHEC

The International Human Epigenome Consortium (IHEC) is a global consortium with the primary goal of providing free access to high-resolution reference human epigenome maps for normal and disease cell types to the research community. The epigenome reference maps will be of great utility in basic and applied research. They are likely to have an immediate impact on the understanding of many diseases, and will hopefully lead to the discovery of new means to treat or manage them. In addition to this work, many members support related projects to improve epigenomic technologies, investigate epigenetic regulation in disease processes, and explore broader gene-environment interactions in human health.

IHEC will facilitate communication among the members and offer a forum for coordination, with the objective of avoiding redundant research efforts, implementing high data quality standards, and thus maximizing efficiency among the scientists working to understand, treat, and prevent diseases. http://ihec-epigenomes.org/

About The British Heart Foundation

Coronary heart disease is the UK's single biggest killer. For over 50 years we've pioneered research that's transformed the lives of people living with heart and circulatory conditions. Our work has been central to the discoveries of vital treatments that are changing the fight against heart disease. But so many people still need our help. From babies born with life-threatening heart problems to the many Mums, Dads and Grandparents who survive a heart attack and endure the daily battles of heart failure. Join our fight for every heartbeat in the UK. Every pound raised, minute of your time and donation to our shops will help make a difference to people's lives. For more information visit https://www.bhf.org.uk

About McGill University

With some 300 buildings, 40,000 students, 250,000 living alumni, and a reputation for excellence that reaches around the globe, McGill has carved out a spot among the world's greatest universities. https://www.mcgill.ca

About NHS Blood and Transplant

NHS Blood and Transplant (NHSBT) is a joint England and Wales Special Health Authority. Its remit includes the provision of a reliable, efficient supply of blood, platelets, plasma and associated services to the NHS in England. It is also the organ donor organisation for the UK and is responsible for matching and allocating donated organs. http://www.nhsbt.nhs.uk/

About UK BioBank

UK Biobank is a major national and international health resource, and a registered charity in its own right, with the aim of improving the prevention, diagnosis and treatment of a wide range of serious and life-threatening illnesses - including cancer, heart diseases, stroke, diabetes, arthritis, osteoporosis, eye disorders, depression and forms of dementia. UK Biobank recruited 500,000 people aged between 40-69 years in 2006-2010 from across the country to take part in this project. They have undergone measures, provided blood, urine and saliva samples for future analysis, detailed information about themselves and agreed to have their health followed. Over many years this will build into a powerful resource to help scientists discover why some people develop particular diseases and others do not. https://www.ukbiobank.ac.uk/

University of Cambridge

The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 90 affiliates of the University have won the Nobel Prize. Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America. The University sits at the heart of one of the world's largest technology clusters. The 'Cambridge Phenomenon' has created 1,500 hi-tech companies, 12 of them valued at over US$1 billion and two at over US$10 billion. Cambridge promotes the interface between academia and business, and has a global reputation for innovation. http://www.cam.ac.uk/

University of Oxford https://www.ox.ac.uk

The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. http://www.sanger.ac.uk/

Wellcome

Wellcome exists to improve health for everyone by helping great ideas to thrive. We're a global charitable foundation, both politically and financially independent. We support scientists and researchers, take on big problems, fuel imaginations and spark debate. http://www.wellcome.ac.uk/

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