Genetic and transcriptomic analyses to determine the aetiopathogenesis of solar urticaria

Background:

Solar urticaria is a rare skin condition affecting only 3 in 100,000 people in the U.K. It causes the development of an allergic rash (hives) only a few minutes after skin is exposed to normal sunlight. The extent of the rash depends on the area of skin exposed and it tends to be confined to a small area. However, if large areas of skin are exposed, e.g., while swimming, people may develop widespread hives and symptoms of a life-threatening allergic reaction (anaphylaxis). People with solar urticaria must therefore protect their skin from sunlight by applying sunscreens and wearing sun-resistant clothing. Medications to treat solar urticaria are also available, but these are helpful in less than half of patients. As a result, solar urticaria has a significant impact on patients' quality of life as they must change their jobs and social activities to avoid sun exposure.

It is known that solar urticaria is caused by activation of specialised cells in the skin, known as mast cells, following exposure to sunlight. However, the mechanisms by which sunlight is able to trigger mast cell activation are unclear. This study will explore mechanisms that could activate mast cells in solar urticaria using a number of different strategies. Better understanding of these mechanisms may help in the identification of new, more effective treatments.

Planned investigations:

1. Solar urticaria often occurs alongside certain diseases. It is known that diseases occurring together tend to share genetic risk factors and can be caused by similar mechanisms. We will collect information about genetic risk factors for these diseases and assess if they are shared by solar urticaria. An important example of this would be allergic conditions such as asthma, eczema and hayfever, which occur in nearly half of patients with solar urticaria. Other examples would include related skin conditions causing hives, and diseases in which the body's immune system attacks normal tissues. By identifying which condition shares the greatest genetic risk with solar urticaria, it may be possible to identify important mechanisms by which mast cells are activated to cause its symptoms.
2. We will take small skin samples from areas of hives and also from normal skin in patients with solar urticaria. We will examine which genes are activated in these samples and compare this to skin from healthy volunteers. By identifying genes that are activated only in skin affected by solar urticaria, we can build a more detailed picture of the skin conditions in which mast cells live. This is important as these conditions may promote activation of mast cells to cause solar urticaria symptoms.
3. We will put information from these investigations together and undertake further specific studies of disease mechanisms in solar urticaria. We will do this by examining skin samples from solar urticaria under a microscope and by using mast cells grown in the laboratory, which can be treated with specific proteins or chemicals and then have changes in their behaviour assessed.

We have collaborated with researchers across the U.K., Europe and Australia to create the largest ever study of solar urticaria. Consequently, we believe this investigation has great potential to improve our understanding of solar urticaria, provide more effective treatments for patients, and improve their quality of life. Importantly, our findings may also be relevant to related skin conditions in which hives are caused by heat, cold, or water exposure and will therefore be of benefit to a wide range of patients.

Background:
Solar urticaria (SU) is a rare, poorly understood skin disease in which normal sunlight triggers mast cell activation and the development of cutaneous wheals. Current evidence supports an underlying genetic architecture that is polygenic. It is frequently associated with atopic disorders and previous experiments suggest that IgE-crosslinking on the mast cell surface by sunlight-activated protein chromophores is a major pathogenic mechanism. However, its epidemiological association with other diseases and evidence of mast cell suppression following ultraviolet irradiation suggest that other modes of mast cell activation and the cutaneous microenvironment may play a role.

Aim: To determine the aetiopathogenesis of SU using genetic and transcriptomic analyses

Objectives:
1. Investigate shared genetic aetiology of SU and associated disorders using polygenic risk scores
2. Undertake transcriptomic analysis of cutaneous gene expression in SU and healthy controls
3. Validate and explore implicated gene products and molecular pathways

Methods:
Genetic aetiology shared by diseases can imply common disease mechanisms. Consequently, polygenic risk scores (PRS) will be generated for atopic disorders and other conditions associated with SU. The association of these PRSs with SU will be compared to ancestry-matched healthy controls. Gene expression in lesional solar-irradiated and control non-irradiated skin biopsies from SU patients will be characterized using bulk RNA-Seq and compared with site-matched solar-irradiated and non-irradiated biopsies from healthy controls. Validation will depend on previous findings, but may include immunohistochemistry/immunofluorescent staining of skin or functional interrogation of human mast cell lines.

Medical and Scientific Impact:
This research has great potential to improve understanding of SU and related urticarias. Such insights may profoundly influence the development of novel therapeutic strategies.