Figure. Regional DNA methylation of ED and PD samples at the 36 determined DMRs with hypomethylation of PD samples suggesting possible overexpression at associated genes.

Peyronie’s disease (PD) is a fibrosing disorder with a prevalence of up to 11% in the United States.¹ This condition impacts sexual functioning due to associated pain, penile curvature, penile shortening, and erectile dysfunction (ED), and also has broader implications through alterations in mental health, interpersonal relationships, quality of life, and overall well-being.^2,3 While PD represents a heterogeneous condition of varying severity, evidence suggests a genetic influence based on its higher prevalence in select populations and association with other fibrosing disorders, such as Dupuytren’s and Ledderhose diseases, which are all inherited in autosomal dominant fashion with variable penetrance.⁴ This evidence supports a pathophysiology centered on a genetic predisposition towards fibrosis in a subset of men, rather than a set of isolated fibrotic conditions brought about by discrete traumatic occurrences.

While a hereditary predisposition to PD suggests that genetic variants may exist, environmentally driven epigenetic factors may also account for differences among individuals with this condition, including the development and progression of PD. Epigenetic regulation involving histone deacetylases (HDAC) has already been implicated in the pathogenesis of multiple fibrotic disorders of the kidneys, bladder, lungs, heart, and liver and has subsequently been found to play a significant role in PD, including the extent of fibrosis that may occur after disease onset.^4,5 One study found that PD model rats receiving injections of adenovirus-encoded HDAC2 small hairpin RNA (ad-HDAC2 shRNA) had regression of fibrotic penile plaque, fewer intralesional inflammatory cells, impaired nuclear translocation of phosphorylated Smad3, inhibited differentiation of fibroblasts into myofibroblasts and reduced collagen production.⁶ This suggests that variations in methylation and subsequent gene expression without overt genetic defects may predispose men to the condition and can be targets for treatment.

Without further research on this topic, our existing therapies remain incompletely effective and focus on symptoms of this condition rather than the underlying causes since no targeted molecular treatments are currently available. The identification of epigenetic changes impacting PD that alter gene expression could facilitate screening for PD prior to symptoms as well as risk stratification of patients. Long term, this type of research could lead to the identification of targeted therapies that can be used to individualize treatment. Our research has focused on investigating whether variations in epigenetic profiles exist for individuals with PD based on DNA methylation assessment to facilitate a more complete understanding of PD, with the eventual goals of identifying epigenetic profiles for risk stratification and developing novel biomarkers and treatments that could offer preventative care and/or improve clinical treatment.

To facilitate this research, tunica albuginea samples were collected from nonplaque tissue during penile prosthesis placement for men with PD and ED, with ED-only samples serving as controls. DNA methylation analyses were performed on homogenized tissue samples via an Illumina Human MethylationEPIC BeadChip v2 array. Using the minfi package in R, beta values were produced for all 936,990 CpG sites for each sample and SWAN normalization was applied. Differentially methylated regions (DMRs) were found via USEQ with a threshold Wilcoxon FDR score of 40.

Analyses conducted between the 10 PD samples and 12 control samples yielded a total of 36 DMRs with 60 total region-gene associations and 5 implicated ­biological processes, including anterior/posterior pattern specification, chordate embryonic development, embryo development (ending in birth or egg hatching), somitogenesis, and pattern specification process. All but 4 of the 36 DMRs between ED and PD sample groups demonstrated hypomethylation of PD samples relative to ED samples (Figure). Each of the implicated biological processes are essential components of the human body’s developmental biology, and the specific region-gene associations suggest pathogenesis may be an early embryonic development. The identification of these changes in nonplaque tissue also suggests a systemic process related to PD that is not isolated to plaque tissue. Additional investigation is necessary to determine the validity of any suggested implications and to determine how these methylation changes may affect RNA sequencing and gene expression.

The findings of this investigation deepen our understanding of PD and will hopefully motivate larger-scale research into the breadth of genetic and epigenetic factors that influence the development of PD. A detailed epigenetic profile of PD will ultimately enable patients and their physicians to create a road map for lifelong health and will lead to improved prevention, diagnosis, and treatment.