Molecular Genetics of Dupuytren´s Disease

Dupuytren’s disease (DD) is a fibromatosis of connective tissue within the palm of the hands. It is characterised by progressive collagen deposition that leads to hardening and thickening of the connective tissue and results in permanent contraction of affected fingers. The aetiology of Dupuytren’s disease is so far unknown and the pathogenesis is favoured by ageing, genetic predisposition, mechanic trauma and possibly other risk factors. Blood and tissue samples of over 850 German and Swiss DD patients were collected in order to analyse the genetics, gene expression patterns and the in vitro behaviour of disease tissue derived fibroblast in 2-D and 3-D models. A genome wide association study (GWAS) with 565 unrelated DD patients and 1,219 controls was performed. Data for 5,204,451 single-nucleotide polymorphisms (SNPs; 186 cases genotyped with Affymetrix Genome-Wide Human SNP Array 6.0 and 379 cases, 1219 controls genotyped with Axiom CEU 1 Array; data imputed with HapMap CEU reference panel) were analyzed for association with DD. SNP rs2290221 on chromosome 7p14, showed the strongest association signal with a p-value of 2.2x10-10 and odds ratio of 2.13. SNP rs2290221 is located intronic of the genes secreted frizzled-related protein 4 (SFRP4) and ependymin related protein 1 (zebrafish) (EPDR1). In addition an integrative replication study with 2,325 Dutch, English and German DD cases and 11,562 controls was performed. It identified nine different susceptibility loci that showed genome-wide significance. Six of these loci contain genes known to be involved in the Wnt/β-catenin signalling pathway. Again the strongest association was seen for the 7p14 locus. Consistent with GWAS findings, a whole genome expression analysis with 12 DD primary disease tissue samples and 12 normal fascia controls revealed upregulation of the Wnt/β-catenin signalling pathway and also changes in mitochondrial function and oxidative stress response in disease tissue. The Wnt signalling pathway is therefore likely to be a key player in the fibromatosis process observed in DD. Primary disease tissue derived fibroblasts at least in part retained their disease associated characteristics in vitro, they exhibited higher proliferation rates and generated strong contraction forces in 3-D collagen gels, and thus present an excellent model for investigating the mechanisms of DD in the context of aging and aging associated diseases.