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Project properties
Title | Epigenetic architecture of Dupuytren’s disease |
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Keywords | Dupuytren's disease (Epi)genetic epidemiology Precision medicine |
Researchers |
prof.dr. P.M.N. Werker dr. Ilja M. Nolte Sophie A. Riesmeijer |
Type of project | MD/PhD programme |
Nature of the research | Genetic epidemiology, bioinformatics |
Fields of study | epidemiology and statistics plastic surgery genetics |
Background / introduction |
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Dupuytren’s disease (DD) is a common fibrotic disorder affecting the hands that causes permanent flexion contractures of the fingers. Standard treatment is aimed at reducing flexion contractures, but no cure exists. Recurrence rates following treatment are high: 21% to 85% in 5 years, depending on type of treatment.(1) Although the aetiology of DD is not well understood, it is recognized as a complex disorder with a strong genetic basis. Environmental factors associated to DD include body mass index, diabetes mellitus, hyperlipidaemia, and frozen shoulder.(2) Genome-wide association studies have identified numerous genetic variants (single nucleotide polymorphisms [SNPs]) for DD.(3) These genetic variants each have a small contribution to genetic risk for DD. Significant genetic correlations have been found between DD and (metabolic) traits and diseases, including type 2 diabetes mellitus, body mass index, and frozen shoulder.(4) Causal relationships between DD and most of these correlated traits are yet to be inferred.(5) Although known genetic factors for DD already explain a substantial portion of the disease variance (26%, unpublished work), there is also still a large part that cannot be explained. One reason for this may be epigenetics (Figure 1). Epigenetics means ‘outside or around the genetics’ and studies how environment and behaviour (e.g. smoking) can cause changes that affect the way your genes work. While genetics study the effects of heritable factors (genes) on a disease, epigenetics study the mechanism driving activity and expression of genes. Epigenetic factors can be transmitted from generation to generation, so a logical next step would therefore be to investigate the influence of epigenetic factors on DD. |
Research question / problem definition |
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In treatment of DD, timing and type of treatment are important factors for risk of recurrence. Choice of these for the individual patient is difficult and currently based on clinical risk characteristics, often before the full extent of their DD phenotype has become apparent. Even though genetic profiling has already proven to be predictive of DD recurrence, its predictive accuracy was insufficient for clinical implementation (unpublished work). Studying epigenetics could help to uncover more genetic mechanisms driving risk for DD and DD recurrence. These epigenetic risk factors can be summarised in a patient’s epigenetic risk profile and in combination with a genetic risk profile, this profile could be incremental to clinical decision making. |
References |
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1. Van Rijssen AL, Ter Linden H, Werker PMN. Five-year results of a randomized clinical trial on treatment in Dupuytren’s disease: Percutaneous needle fasciotomy versus limited fasciectomy. Plastic and Reconstructive Surgery. 2012;129(2):469–77. 2. Alser OH, Kuo RYL, Furniss D. Nongenetic factors associated with dupuytren’s disease: A systematic review. Plastic and Reconstructive Surgery. 2020;799–807. 3. Ng M, Thakkar D, Southam L, Werker P, Ophoff R, Becker K, et al. A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis. American Journal of Human Genetics. 2017;101(3):417–27. 4. Major M, Freund MK, Burch KS, Mancuso N, Ng M, Furniss D, et al. Integrative analysis of Dupuytren’s disease identifies novel risk locus and reveals a shared genetic etiology with BMI. Genetic Epidemiology. 2019;43(6):629–45. 5. Majeed M, Wiberg A, Ng M, Holmes M v, Furniss D. The relationship between body mass index and the risk of development of Dupuytren’s disease: a Mendelian randomization study. J Hand Surg Eur Vol. 2021;46(4):406–10. 6. Shah S, Bonder MJ, Marioni RE, Zhu Z, McRae AF, Zhernakova A, et al. Improving Phenotypic Prediction by Combining Genetic and Epigenetic Associations. American Journal of Human Genetics. 2015;97(1):75–85. |