Cambridge
Biomedical Research Centre

Publication: Journal of the American College of Cardiology

Michael Inouye, Gad Abraham, Christopher P. Nelson, Angela M. Wood, Michael J. Sweeting, Frank Dudbridge, Florence Y. Lai, Stephen Kaptoge, Marta Brozynska, Tingting Wang, Shu Ye, Thomas R. Webb, Martin K. Rutter, Ioanna Tzoulaki,Riyaz S. Patel, Ruth J.F. Loos, Bernard Keavney, Harry Hemingway, John Thompson, Hugh Watkins, Panos Deloukas,Emanuele Di Angelantonio, Adam S. Butterworth, John Danesh, Nilesh J. Samani

Summary:

Genetic factors have long been known to be major contributors of someone’s risk of developing coronary heart disease – the leading cause of heart attacks. Currently to identify those at risk doctors use scores based on lifestyle and clinical conditions associated with coronary heart disease such as cholesterol level, blood pressure, diabetes and smoking. But these scores are imprecise, age-dependent and miss a large proportion of people who appear ‘healthy’, but will still develop the disease.

The ‘big-data’ GRS technique takes into account 1.7 million genetic variants in a person’s DNA to calculate their underlying genetic risk for coronary heart disease.

The team analysed genomic data of nearly half a million people from the UK Biobank research project aged between 40-69 years. This included over 22,000 people who had coronary heart disease.

The GRS was better at predicting someone’s risk of developing heart disease than each of the classic risk factors for coronary heart disease alone. The ability of the GRS to predict coronary heart disease was also largely independent of these known risk factors. This showed that the genes which increase the risk of coronary heart disease don’t simply work by elevating blood pressure or cholesterol, for example.

People with a genomic risk score in the top 20 per cent of the population were over four-times more likely to develop coronary heart disease than someone with a genomic risk score in the bottom 20 per cent. Read the full press release

Publication: Nature Genetics

Geoff Macintyre, Teodora E. Goranova, Dilrini De Silva, Darren Ennis, Anna M. Piskorz, Matthew Eldridge, Daoud Sie, Liz-Anne Lewsley, Aishah Hanif, Cheryl Wilson, Suzanne Dowson, Rosalind M. Glasspool, Michelle Lockley, Elly Brockbank, Ana Montes, Axel Walther, Sudha Sundar, Richard Edmondson, Geoff D. Hall, Andrew Clamp, Charlie Gourley, Marcia Hall, Christina Fotopoulou, Hani Gabra, James Paul, Anna Supernat, David Millan, Aoisha Hoyle, Gareth Bryson, Craig Nourse, Laura Mincarelli, Luis Navarro Sanchez, Bauke Ylstra, Mercedes Jimenez-Linan, Luiza Moore, Oliver Hofmann, Florian Markowetz, Iain A. McNeish and James D. Brenton

Summary:

Researchers have found distinct patterns of DNA rearrangement that are linked to patient outcomes.

In this study of ovarian cancer samples from over 500 women, the research team harnessed big data processing techniques to look for broad patterns in the genetic readouts from ovarian cancer cells.

Rather than focusing on the detail of each individual mistake in the DNA, they designed powerful computer algorithms to scan the genetic data, finding seven distinct patterns.

They showed that each pattern, or “signature”, represented a different mechanism of DNA mutation. Taken together, these signatures were able to make sense of the chaos seen in ovarian cancer genomes. Read the full story here

Publication: The Lancet

Michael J Sweeting, Katya L Masconi, PhD, Edmund Jones, PhD, Pinar Ulug, PhD, Matthew J Glover, MSc, Prof Jonathan A Michaels, MChir, Prof Matthew J Bown, MD, Prof Janet T Powell, MD, Prof Simon G Thompson, DSc

Summary:

The NHS introduced ultrasound screening in men aged 65 and over in 2009 to detect and treat the condition – which arises when the main blood vessel swells in the abdomen, and is symptomless until the point of rupture. Since the launch, the programme has been successfully screening and identifying men at risk of an AAA.

Researchers wanted to see if UK women – who are less likely to have AAAs – could also benefit from a similar screening programme. Read the full press release here

Publication: The Lancet

Gemma D Banham, MRCP(UK), Shaun M Flint, FRACP,  Nicholas Torpey, FRCP, Paul A Lyons, PhD, Don N Shanahan, MSc, Adele Gibson, BSc, Prof Christopher J E Watson, FRCS, Ann-Marie O’Sullivan, MRes, Joseph A Chadwick, Katie E Foster, PhD, Rachel B Jones, FRCP, Luke R Devey, MRCSEd, Anna Richards, MRCP(UK), Prof Lars-Peter Erwig, MD, Prof Caroline O Savage,FMedSci, Prof Kenneth G C Smith, FMedSci, Robert B Henderson, PhD, Menna R Clatworthy, FRCP†,

Summary:

Transplantation is the best form of treatment for most patients with end-stage renal failure, but long-term graft survival is limited by the development of antibodies against the graft. There is therefore a major unmet need to find immunosuppressants that target humoral alloimmunity.

Researchers investigated the use of Belimumab, a monoclonal antibody that binds the B cell pro-survival cytokine BAFF, in kidney transplant recipients.

The study found that the use of belimumab was not associated with any excess risk of infection, and led to a reduction in antibody-producing plasmablasts, activated memory B cells, new IgG antibody formation and in non-HLA IgG antibodies associated with poor graft outcomes. Remarkably, belimumab treatment spared regulatory B cells – a cell type associated with transplant tolerance, with an increase in IL10-producing B cells observed.

Publication: The Lancet

Angela M Wood PhD, P, Stephen Kaptoge, PhD, Adam S Butterworth, PhD, Peter Willeit, MD, Samantha Warnakula, PhD, Thomas Bolton, MMath, Ellie Paige, PhD, Dirk S Paul, PhD, Michael Sweeting, PhD, Stephen Burgess, PhD, Steven Bell, PhD, William Astle, PhD, David Stevens, MSc, Albert Koulman, PhD, Randi M Selmer, PhD, Prof W M Monique Verschuren, PhD, Prof Shinichi Sato, MD, Prof Inger Njølstad, MD, Prof Mark Woodward, PhD, Prof Veikko Salomaa, MD, Prof Børge G Nordestgaard, MD, Prof Bu B Yeap, MBBS, Prof Astrid Fletcher, PhD, Prof Olle Melander, MD, Prof Lewis H Kuller, MD, Beverley Balkau, PhD, Prof Michael Marmot, FMedSci, Prof Wolfgang Koenig, MD, Prof Edoardo Casiglia, MD, Prof Cyrus Cooper, FMedSci, Volker Arndt, MD, Prof Oscar H Franco, MD, Patrik Wennberg, MD, Prof John Gallacher, PhD, Agustín Gómez de la Cámara, MD, Prof Henry Völzke, MD, Christina C Dahm, PhD, Caroline E Dale, PhD, Manuela M Bergmann, PhD, Carlos J Crespo, PhD, Prof Yvonne T van der Schouw, PhD, Prof Rudolf Kaaks, MD, Leon A Simons, MD, Pagona Lagiou, MD, Josje D Schoufour, PhD, Jolanda M A Boer, PhD, Prof Timothy J Key, DPhil, Beatriz Rodriguez, MD, Conchi Moreno-Iribas, PhD, Karina W Davidson, PhD, James O Taylor, MD, Carlotta Sacerdote, PhD, Prof Robert B Wallace, MD, J Ramon Quiros, MD, Prof Rosario Tumino, MD, Dan G Blazer II, MD, Prof Allan Linneberg, MD, Makoto Daimon, MD, Salvatore Panico, MD, Barbara Howard, PhD, Guri Skeie, PhD, Prof Timo Strandberg, MD, Prof Elisabete Weiderpass, PhD, Prof Paul J Nietert, PhD, Prof Bruce M Psaty, MD, Prof Daan Kromhout, PhD, Elena Salamanca-Fernandez, MSc, Prof Stefan Kiechl, MD, Prof Harlan M Krumholz, MD, Sara Grioni, BSc, Domenico Palli, MD, José M Huerta, PhD, Prof Jackie Price, MD, Prof Johan Sundström, MD, Larraitz Arriola, MD, Prof Hisatomi Arima, MD, Ruth C Travis, DPhil, Prof Demosthenes B Panagiotakos, PhD, Anna Karakatsani, MD, Prof Antonia Trichopoulou, MD, Tilman Kühn, PhD, Prof Diederick E Grobbee, MD, Elizabeth Barrett-Connor, MD, Natasja van Schoor, MD, Prof Heiner Boeing, PhD, Prof Kim Overvad, MD, Prof Jussi Kauhanen, MD, Prof Nick Wareham, MD, Claudia Langenberg, MD, Prof Nita Forouhi, PhD, Maria Wennberg, PhD, Prof Jean-Pierre Després, DPhil, Prof Mary Cushman, MD, Jackie A Cooper, MSc, Prof Carlos J Rodriguez, MD, Masaru Sakurai, MD, Jonathan E Shaw, PhD, Prof Matthew Knuiman, PhD, Trudy Voortman, PhD, Prof Christa Meisinger, MD, Anne Tjønneland, MD, Prof Hermann Brenner, MD, Luigi Palmieri, PhD, Jean Dallongeville, MD, Prof Eric J Brunner, PhD, Prof Gerd Assmann, MD, Maurizio Trevisan, MD, Richard F Gillum, MD, Prof Ian Ford, PhD, Prof Naveed Sattar, FMedSci, Mariana Lazo, MD, Prof Simon G Thompson, FMedSci, Pietro Ferrari, PhD, Prof David A Leon, PhD, Prof George Davey Smith, MD, Prof Richard Peto, FRS, Prof Rod Jackson, PhD, Prof Emily Banks, PhD, Emanuele Di Angelantonio, MD, Prof John Danesh,

Summary:

Regularly drinking more than the recommended UK guidelines for alcohol could take years off your life, according to new research from the University of Cambridge. The study shows that drinking more alcohol is associated with a higher risk of stroke, fatal aneurysm, heart failure and death.

Publication: Nature Communications

Stefan Gräf, Matthias Haimel, Marta Bleda, Charaka Hadinnapola, Laura Southgate, Wei Li, Joshua Hodgson, Bin Liu, Richard M. Salmon, Mark Southwood, Rajiv D. Machado, Jennifer M. Martin, Carmen M. Treacy, Katherine Yates, Louise C. Daugherty, Olga Shamardina, Deborah Whitehorn, Simon Holden, Micheala Aldred, Harm J. Bogaard, Colin Church, Gerry Coghlan, Robin Condliffe, Paul A. Corris, Cesare Danesino, Mélanie Eyries, Henning Gall, Stefano Ghio, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Arjan C. Houweling, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Robert V. MacKenzie Ross, Shahin Moledina, David Montani, Michael Newnham, Andrea Olschewski, Horst Olschewski, Andrew J. Peacock, Joanna Pepke-Zaba, Inga Prokopenko, Christopher J. Rhodes, Laura Scelsi, Werner Seeger, Florent Soubrier, Dan F. Stein, Jay Suntharalingam, Emilia M. Swietlik, Mark R. Toshner, David A. van Heel, Anton Vonk Noordegraaf, Quinten Waisfisz, John Wharton, Stephen J. Wort, Willem H. Ouwehand, Nicole Soranzo, Allan Lawrie, Paul D. Upton, Martin R. Wilkins, Richard C. Trembath & Nicholas W. Morrell

Summary:

Pulmonary Arterial Hypertension (PAH) is a fatal lung disease and causes the walls of the arteries become thick and stiff, narrowing the space for blood to pass through and increasing blood pressure then leading to heart failure.

The disease kills 50% of those affected within five years, but little was known about what caused the condition in some people. Now experts say they have discovered five genes that cause the illness and could pave the way for more treatments.

Scientists carried out the largest ever genetic study of the disease by analysing the genomes – the unique sequence of a person’s DNA – of more than 1,000 PAH patients for whom the cause of the illness was unknown.

They found that mutations in five genes were responsible for causing the illness in these people, including in four genes that were not previously known to be involved in the disease. In people with the condition these genes fail to effectively produce the proteins that are required for the structure, function and regulation of the body’s tissues, researchers found.

Publication: Annals

Linda M. O’Keeffe, PhD; Anna Ramond, DPharm; Clare Oliver-Williams, PhD; Peter Willeit, MD; Ellie Paige, PhD; Patrick Trotter, MBChB; Jonathan Evans, MBChB; Jonas Wadström, MD; Michael Nicholson, MD; Dave Collett, PhD; Emanuele Di Angelantonio, MD

Summary:

Living kidney donors are not at increased risk for some health outcomes previously of concern, but do seem at risk for worse blood pressure and kidney function than nondonors. In addition, female donors seem to be at increased risk for preeclampsia.

A team lead by researchers reviewed 52 published studies comprising more than 100,000 living kidney donors and more than 110,000 nondonors to assess the mid- and long-term health risks associated with living kidney donation in adults.

The data showed that kidney donors had higher diastolic blood pressure, poorer renal function, and higher risk for ESRD than nondonors. Female donors had an almost two-fold higher risk than nondonors for pregnancy-related complications, such as preeclampsia.

There was no evidence that living kidney donors had higher risk for mortality, cardiovascular disease, or type 2 diabetes, or reduced quality of life.

Publication: Nature Cell Biology

Vasileios I. Floros, Angela Pyle, Sabine Dietmann, Wei Wei, Walfred W. C. Tang, Naoko Irie, Brendan Payne, Antonio Capalbo, Laila Noli, Jonathan Coxhead, Gavin Hudson, Moira Crosier, Henrik Strahl, Yacoub Khalaf, Mitinori Saitou, Dusko Ilic, M. Azim Surani & Patrick F. Chinnery

 15 Jan 2018; DOI: 10.1038/41556-017-0017-8

Summary:

Researchers have shown for the first time how children can inherit a severe – potentially fatal – mitochondrial disease from a healthy mother. The study reveals that healthy people harbour mutations in their mitochondrial DNA and explains how cases of severe mitochondrial disease can appear unexpectedly in previously unaffected families.

Mitochondrial diseases caused by mutations in mitochondrial DNA are rare, affecting approximately 1 in 10,000 births, but can cause severe conditions. Mitochondria are the powerhouses inside our cells, producing energy and carrying their own DNA instructions (separate from the DNA in the nucleus of every cell) and are inherited from a person’s mother via the egg.

In this study, the researchers found that a variety of mutations were present in the mitochondrial DNA in the developing egg cells of all 12 of the human embryos studied, showing that low levels of mitochondrial DNA mutations are carried by healthy humans.

Publication: Brain

Thomas E Cope, Timothy Rittman, Robin J Borchert, P Simon, JonesDeniz Vatansever, Kieren Allinson Luca Passamonti, Patricia Vazquez Rodriguez, W Richard Bevan-Jones, John T O’Brien, James B Rowe

Publication: J Neurol

Underwood BR, Green-Thompson ZW, Pugh PJ, Lazic SE, Mason SL4, Griffin J, Jones PS, Rowe JB, Rubinsztein DC7,4, Barker RA.

2017 Oct 26. doi: 10.1007/s00415-017-8647-0. [Epub ahead of print]

Publication: The Lancet Neurology

Prof Andrew I R Maas*,’Correspondence information about the author Prof Andrew I R MaasEmail the author Prof Andrew I R Maas, Prof David K Menon*,’Correspondence information about the author Prof David K MenonEmail the author Prof David K Menon, P David Adelson, Nada Andelic, Michael J Bell, Antonio Belli, Peter Bragge, Alexandra Brazinova, András Büki, Randall M Chesnut, Giuseppe Citerio, Mark Coburn, D Jamie Cooper, A Tamara Crowder, Endre Czeiter, Marek Czosnyka, Ramon Diaz-Arrastia, Jens P Dreier, Ann-Christine Duhaime, Ari Ercole, Thomas A van Essen, Valery L Feigin, Guoyi Gao, Joseph Giacino, Laura E Gonzalez-Lara, Russell L Gruen, Deepak Gupta, Jed A Hartings, Sean Hill, Ji-yao Jiang, Naomi Ketharanathan, Erwin J O Kompanje, Linda Lanyon, Steven Laureys, Fiona Lecky, Harvey Levin, Hester F Lingsma, Marc Maegele, Marek Majdan, Geoffrey Manley, Jill Marsteller, Luciana Mascia, Charles McFadyen, Stefania Mondello, Virginia Newcombe, Aarno Palotie, Paul M Parizel, Wilco Peul, James Piercy, Suzanne Polinder, Louis Puybasset, Todd E Rasmussen, Rolf Rossaint, Peter Smielewski, Jeannette Söderberg, Simon J Stanworth, Murray B Stein, Nicole von Steinbüchel, William Stewart, Ewout W Steyerberg, Nino Stocchetti, Anneliese Synnot, Braden Te Ao, Olli Tenovuo, Alice Theadom, Dick Tibboel, Walter Videtta, Kevin K W Wang, W Huw Williams, Lindsay Wilson, Kristine Yaffe for the show InTBIR Participants and Investigators

Publication: Proceedings of National Academy of Sciences

Deniz Vatansever, David K. Menon, and Emmanuel A. Stamatakis