The functional annotation of psoriasis susceptibility alleles (V1)
Research type
Research Study
Full title
The functional annotation of psoriasis susceptibility alleles
IRAS ID
164487
Contact name
Jonathan Barker
Contact email
Duration of Study in the UK
10 years, 0 months, 1 days
Research summary
Psoriasis is a common, chronic, stigmatising immune-mediated skin disease which causes great morbidity and has a detrimental effect on the quality of life of patients and families. Current therapies are non-curative and associated with significant side effects. There are multiple clinical subtypes of psoriasis, which likely have unique immunogenetic profiles. Psoriasis vulgaris, which is characterised by red, scaling skin plaques, is the most common subtype and affects 85 to 95% of patients. Other subtypes include guttate psoriasis, nail psoriasis and pustular variants such as generalised pustular psoriasis and palmoplantarpustulosis.
Whilst the exact cause of psoriasis remains unclear, risk of the disorder is markedly increased in near relatives of patients. The majority of research to date has investigated the early onset (before age 40) form of psoriasis vulgaris (type 1 psoriasis). Large areas of the genome that confer susceptibility to psoriasis vulgaris have been discovered by genetic association studies. However, each region spans numerous genes, many of which are involved in immune functions, and there is a current need to identify those genes that contribute to the development of disease. Once the causal alleles for psoriasis have been determined, functional studies using tissues relevant to the disease (e.g. skin, blood) will be essential in improving our understanding of the molecular mechanisms involved in disease pathogenesis and guiding the development of more effective and less toxic therapies.
Recent research investigating generalised pustular psoriasis has identified rare pathogenic mutations in IL-36RN and AP1S3. IL36RN is involved in regulation of IL-1 and AP1S3 promotes the induction of type I interferon, which down-regulates IL-1 levels. Although the studies support a role for IL-1 antagonists as a treatment for generalised pustular psoriasis, which has showed promise in recent pilot data, mutations in these genes only account for a minority of disease cases. Therefore, the recruitment of extended patient resources is required to enable the discovery of further disease genes and characterisation of their functional consequence.
The recruitment of affected patients who have been deeply phenotyped, and healthy controls, will enable the identification of the causal genetic variants that contribute to susceptibility to specific subtypes of psoriasis. The ascertainment of such cases and controls will occur in phase 1 of the study (see protocol section 2.2). We will then determine the biological effect of the variants on inflammatory pathways and establish how these changes may result in the disease phenotype. This will require tissue such as skin biopsies from patients and healthy volunteers. Hence relevant subjects (cases and controls) will be recalled on the basis of their genotypes in phase 2 of the study and asked to provide biological samples for the purposes of functional studies.
To determine the functional and phenotypic impacts of gene inactivation and thereby gain further critical insights into the pathogenesis of psoriasis, we will utilise two unique cohorts comprising individuals who are enriched for naturally occurring loss of function genetic variants by virtue of parental relatedness. The two large scale community-based studies 'Born in Bradford' (BiB) and 'East London Genes and Health' (ELG&H) comprise Bradford or East London (respectively) residents of (British-) Pakistani and Bangladeshi origin. Parental relatedness is common in these two UK ethnic groups. The studies involve collection of phenotype and genotype data (exome sequencing) and participants have provided consent for recall for further research studies. Hence in phase 2 of the study, we will also recruit individuals from BiB and ELG&H with naturally occurring loss of function variants in psoriasis-associated genes. Ex-vivo experiments will be performed on sampled tissue from these subjects. We will also recruit controls from within the two cohorts i.e. individuals without variants in psoriasis-associated genes in phase 2.
REC name
London - Chelsea Research Ethics Committee
REC reference
14/LO/2169
Date of REC Opinion
20 Jan 2015
REC opinion
Further Information Favourable Opinion