DNA copy number variations at chromosome 7p14.1 and chromosome 14q11.2 are associated with dupuytren's disease: potential role for MMP and Wnt signaling pathway.

Background: Dupuytren's disease is a common fibroproliferative disorder with an unknown etiology. Emerging evidence suggests a strong genetic component involved in the manifestation of the disease. This study aims to investigate the potential involvement of copy number variations in Dupuytren's disease pathogenesis.

Methods: Array-based comparative genomic hybridization (NimbleGen Human CGH 2.1 M) was utilized to compare DNA from (1) nodules versus internal control (patient's blood; n = 4) and (2) nodules (n = 4) versus external control (commercial reference DNA pooled from 10 donors). Analysis was carried out using Nexus 5.1 (BioDiscovery, El Segundo, Calif.) with the inclusion of additional results from previously published array-based comparative genomic hybridization. Copy number variations were considered to be common in Dupuytren's disease if the overlap was statistically significant and they were present in the majority (75 to 87.5 percent when compared with controls) of Dupuytren's disease nodules. The copy number variations loci were also compared with recently published genome wide-association studies. Common copy number variations were further validated using quantitative polymerase chain reaction. DNA from 25 Dupuytren's disease cases and 30 external controls were used in the quantitative polymerase chain reaction validation. In addition, gene expression was compared between Dupuytren's disease nodules and internal controls (transverse palmar fascia; n = 7).

Results: Five common copy number variations, on chromosome 17q12, 1p31.1, 20p13, 7p14.1, and 14q11.2, were identified by array-based comparative genomic hybridization. Significantly higher copy numbers of copy number variations at chromosome 7p14.1 and 14q11.2 in Dupuytren's disease were confirmed in quantitative polymerase chain reaction validation. Matrix metalloproteinase-14 and secreted frizzled-related protein 4 (near a polymorphism recently associated with Dupuytren's disease) were significantly up-regulated in nodules.

Conclusion: This study demonstrated an association between Dupuytren's disease and copy number variations at chromosomes 7p14.1 and 14q11.2.