Identification of biomarkers and whole genome scanning in Dupuytren's Disease

• Main Author: Hindocha, Sandip
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: 2014
• Subjects: Iceland
• Online Access: https://research.manchester.ac.uk/en/studentTheses/465cbe01-f3d6-4b1a-9e48-ff3c0c42f5c8; https://pure.manchester.ac.uk/ws/files/54547222/FULL_TEXT.PDF

Background: Dupuytren's Disease (DD) is a common fibroproliferative disease of unknown origin affecting the hand. The hypotheses of this thesis are; i) DD is a complex polygenic disease and ii) the cells that comprise DD tissue may be derived not only from fascia but also from fat and dermis. On this basis, the overall aims of this thesis were to: ia) estimate the level of penetrance in a UK DD population; ib) present the largest DD family available to date (from Iceland) and attempt linkage analysis following whole genomic scanning; ii) observe stem cell markers as potential biomarkers in DD fascia, fat and skin compared to appropriate controls. Methods: Patients diagnosed with DD (n = 135) were randomly selected from hospitals in the UK. One family was identified in Reykjavik, Iceland. Family pedigrees were compiled for each patient and subsequently analysed to calculate a revised sibling recurrence risk ratio (Gammas) and estimate the level of penetrance. Members of the Icelandic family from whom DNA was available were genotyped using the Affymetrix 6.0 SNP chip and linkage analysis performed to identify susceptible genetic regions for DD. Biopsies of DD patients (n=9) with digital fixed flexion deformity were taken at operation from the diseased cord, nodule, peri-nodular fat, distant palmar fat and skin. Fluorescence Activated Cell Sorting (FACS), immunohistochemistry and Quantitative Real Time Polymerase Chain reaction (QRT-PCR) were used to identify expression of five mesenchymal (CD's 13, 29, 44, 90, 166) and two haematopoietic (CD's 34,117) stem cell markers.Results: ia) The DD status of 1156 relatives of the 135 probands was established. Patients with a family history had a greater severity of disease than those who did not (p