Identification and functional characterization of genetic risk factors in palmoplantar pustulosis

• Applicant: Professorin Dr. Ulrike Hüffmeier
• Subject Area: Human Genetics ; Dermatology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418120092

Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease that belongs to the rarer forms of psoriasis. PPP is characterized by sterile, neutrophil-filled pustules of the palms and soles. The majority of patients are female and smoke/ previously smoked. Most patients are sporadic cases, while 18-30% of patients have a positive family history for psoriasis. A significant subset of PPP patients have additional, more common psoriatic forms, e.g. psoriasis vulgaris (PsV). Not a single reliably validated genetic risk factor for PPP has been identified yet, and the pathogenesis is largely unsolved. The therapy of PPP is based on the one for PsV, although few controlled studies have been performed and patients respond to therapeutics less consistently. In order to elucidate the pathogenesis of PPP, whole genome sequencing (WGS) will be performed in 100 PPP patients. Bioinformatic processing and analysis of WGS will be performed as recommended by the GATK Best Practices and several copy number (CN) algorithms. Single nucleotide variants in overlapping genes and CN variants affecting those candidate genes will be analyzed following monogenic and oligogenic inheritance models, as these inheritance models have been shown to be most appropriate in other rare pustular psoriasis forms. Expression and open chromatin studies of skin and neutrophils will be used to prioritize genetic variants, furthermore pathway analyses and molecular modelling of candidate variants. Variants in RNA-coding genes and non-coding variants will also be prioritized by expression and open chromatin data in skin and neutrophils, while enrichments analyses of further functional chromatin data - available in publicly available databases - will be valuable to classify candidate variants in non-coding regions further. A European case control study group of another 720 independent patients and >700 controls, respectively, will serve as a replication group and will be analyzed by targeted massively parallel sequencing (smMIP based sequencing). Most frequent and most interesting candidate genes/ genomic loci will be characterized in functional studies on RNA, tissue of patients and by cell-based assays to uncover relevant signaling pathways in PPP. Those genetic risk factors will be attractive starting-points for new immune-modulating therapies.

• DFG Programme: Research Grants