Position(s): University of Cambridge Professor of Experimental Haematology, Honorary Faculty member Wellcome Trust Sanger Institute, Honorary NHSBT Consultant in Haematology.
Email: Debra Fletcher (Business Manager): df296@cam.ac.uk
Tel.: +44 (0)1223 588018 (NHSBT featurenet 48018)
Background
The NHS Blood and Transplant (NHSBT) research group, led by Professor Willem Ouwehand, is embedded in the Department of Haematology at the University of Cambridge and collaborates with the Wellcome Trust Sanger Institute (WTSI) and the European Bioinformatics Institute (EBI). The group’s program of research in megakaryocyte and platelet biology and genomics is one of the largest in Europe and focuses primarily on the relationship between sequence variation in genes transcribed in megakaryocytes and the volume, count and function of platelets. A multidisciplinary team with skills in molecular biology, protein biochemistry, antibody engineering, genomics, and bioinformatics work together on different aspects of human platelets.
Group leaders:
- Mr Steve Garner: Platelet Function Quantitative Trait Loci
- Dr Pete Smethurst: Platelet Function Quantitative Trait Loci, Platelet Biology
- Dr Jennifer Sambrook: Cambridge BioResource
Platelets in Health and Disease
Platelets are the second most abundant cell in the blood and are pivotal to maintain integrity of the arterial vessel wall. One hundred billion platelets are made daily from stem cells in the bone marrow by a process called megakaryopoiesis. This process is highly controlled by our genes so that total platelet count, as well as the volume and the haemostatic function of each platelet are tightly regulated within normal ranges. Platelets are critical in the pathophysiology of cardiovascular diseases like heart attacks and stroke.
Platelet and Megakaryocyte Biology and Genomics
The main aim of the research is to discover genes that control the count, volume, and function of platelets and to develop innovative methods to interrogate platelet function and to apply this knowledge in the clinical setting. The volume, count and function of platelets vary widely in the normal healthy population and all three traits are highly heritable. The discovery of genes that regulate the count and volume of platelets by genome-wide association studies provides novel insights in key regulators of megakaryopoiesis and platelet formation. This information is used in a new project that aims to generate platelets from pluripotent stem cells in the laboratory. In addition, we perform genetic association studies that aim to identify common and rare sequence variants that regulate platelet function.
Cambridge BioResource
The Cambridge BioResource is a local cohort of 10,000 healthy volunteers who have consented to participate in genotype-phenotype association studies. Eight thousand blood donors have been enrolled by the NHS Blood and Transplant as volunteers. Subsequent phase II studies currently focus on genes regulating platelet volume and count, Type I diabetes, Crohn’s disease and altered leucocyte function. The Cambridge BioResource is an exciting initiative of the University of Cambridge Clinical School in close partnership with NHS Blood and Transplant and the Medical Research Council.
The Wellcome Trust Case Control Consortium (WTCCC)
The WTCCC project is a national collaboration between 24 leading UK genetic groups. In 2007 the WTCCC completed the first-ever comprehensive genome-wide association study (GWAS) of 17,000 DNA samples from 14,000 patients suffering from Type I and Type II diabetes, coronary artery disease, hypertension, inflammatory bowel disorder, rheumatoid arthritis and bipolar disorder (2000 samples each) and 3000 common controls. The key contribution by our group has been the establishment of the first-ever large-scale DNA repository of UK-wide common controls (the UK Blood Service Collection of Common Controls, UKBS-CC collection) and the associated laboratory and bioinformatics support to maintain and utilise this unique resource. The UKBS-CC collection encompasses DNA samples from 3000 UK blood donors in England, Scotland and Wales, and is currently available to the academic and NHS community as a reference resource for future GWAS and candidate gene studies.
Blood Cell Immunology
On average, sequence variation in the human genome amounts to one single nucleotide polymorphisms (SNP) for every 1000 bases. Human Platelet Antigens (HPA) are immunogenic single amino acid polymorphisms in platelet membrane glycoproteins. Immunisation against HPAs may result from pregnancy, transfusion and transplantation. Research in platelet immunology has progressed with the development of recombinant HPAs for alloantibody detection, discovery of the genetic basis of novel HPAs, description of the current treatment of fetal-maternal alloimmune thrombocytopenia and development of an engineered therapeutic human antibody against HPA-1a. Studies in platelet immunology are performed in close collaboration with the NHS Blood and Transplant platelet immunology laboratory at NHSBT Filton in Bristol.
NHSBT testing laboratories phenotype large numbers of donor samples for the minor red cell blood groups by classic haemagglutination on a dialy basis. However, the genetic basis of most clinically relevant blood groups on red cells has been resolved. The majority of these blood groups are encoded for by single nucleotide polymorphisms. A research project is currently underway to evaluate whether the phenotyping for minor groups can be replaced by DNA-based genotyping methods. This project will address whether genotyping for minor groups is both as reliable as phenotyping and cost-effective for typing donors and patients.
Funding
The research in the Ouwehand group is funded by the British Heart Foundation, European Commission, The Evelyn Trust, National Institute of Health Research, NHS Blood and Transplant and the Wellcome Trust.