Genetics of Pemphigoid Diseases in Humans

Although ample evidence suggests that PDs are partially genetically determined, among others, by certain HLA haplotypes, IL-1β gene variants, and copy number variations of Fcγ receptor genes, a systematic and comprehensive genetic study of PD patients, including a genome-wide association study (GWAS), has never been conducted, among others due to the paucity in well-characterized PD patient cohorts of sufficient size. We have accumulated in recent years a cohort of meanwhile 500 BP patients, which has already allowed us to conduct a preliminary GWAS. Through the establishment of the CRU Pemphigoid Diseases, we will considerably extend this cohort in the next couple of years. We will run the first genome-wide association study (GWAS) in this cohort including replication of prioritized genes, including those in the scientific focus of other CRU projects, by targeted sequencing. In addition, we will profile mRNA expression in BP skin lesions and contrast these expression profiles to that in clinically unaffected skin as well as to that in healthy controls, thus identifying all genes active in the skin in BP and measuring changes in their activity induced by disease. Combing genomic and transcriptomic data, we will, in collaboration with the Z2-Project, model the processes driving PD skin inflammation and identify molecular pathways likely to be significantly involved in disease by a systems medicine approach.
These results will also evaluate the relevance of molecular pathways under scrutiny in other CRU projects for human BP patients. Furthermore, we will merge genomic data with microbiota data to address the relevance of the previously in mouse models described interactions between genes – microbiota – and PD skin inflammation for the human situation.  The functional relevance of select newly identified pathways will be addressed in this funding period in collaboration with other CRU projects providing the appropriate scientific expertise or will be addressed in future projects of the second CRU funding period.