NOVID – Role of DNA non-coding variants in von Willebrand disease

Summary

Von Willebrand factor (VWF) is a large protein that helps the blood to clot. Most VWF in the body is produced in the cells that line blood vessels, called endothelial cells, and it is then released into the blood. Additionally, a much smaller amount of VWF is found in tiny blood cells, called platelets, that also help to form a clot in case of injury.

Sub-optimal levels or function of circulating VWF are the cause of von Willebrand disease (VWD), an inherited bleeding disorder that affects more than 10,000 people in the UK. VWD symptoms include heavy menstrual periods and life-threatening haemorrhages in situations such as trauma, surgery and childbirth.

The VWF gene can have changes in its DNA sequence, known as variants, which inactivate the function of the VWF protein. The existing NHS DNA test, focussed on the protein-producing portion of the gene, provides a diagnosis for three-quarters of VWD patients. However, there are patients in which no genetic cause of VWD has been identified. Therefore, new diagnostic approaches may help to improve patient care.

VWF, like most genes, has sections of DNA within and beside it known as regulatory elements. These act as ‘dimmers & switches’ modulating the amount of gene product made. We have identified the position of these regulatory elements for the VWF gene. We have also shown that a common variant in the DNA sequence of one of the regulatory elements leads to an increase in the amount of VWF in platelets. Our next step is to investigate whether rare variants, with large effects, in VWF regulatory elements, result in VWD. This could result in improvements in the DNA test for this condition, potentially providing a genetic explanation to the remaining quarter of patients who currently do not have a confirmed molecular diagnosis.