Decoding the Genetic Complexity of Psoriasis: Implications for Clinical Practice

Recent advancements in genetic, epigenetic, and proteomic research are rapidly evolving approaches to psoriasis management, which is much needed for the 60 million people affected globally.

And while the exact cause of psoriasis remains elusive, it is known that genetics play a significant role. Fortunately, recent advancements in genetic research have shed new light on this complex disorder, which offers hope for improved patient care approaches.

Genetic and Epigenetic Landscape

Genome-wide association studies (GWAS) have expanded our understanding of the genetic landscape of psoriasis. Over 109 susceptibility loci have been identified, and most are attributed with the MHC I region, remaining the strongest genetic determinant as it accounts for 66 percent of genetic risk.

However, the complex interplay between genes and the environment necessitates exploring epigenetic modifications, which can act as a bridge between our genetic makeup and environmental triggers.

Epigenetic modifications influence gene expression without altering the DNA sequence itself. In psoriasis, these modifications play a crucial role. In fact, studies have revealed alterations in DNA methylation patterns, histone modifications, and non-coding RNA expression in psoriatic lesions compared to healthy skin.

For instance, a recent discovery identified differentially methylated regions associated with genes involved in immune response and skin cell differentiation. Additionally, research has highlighted the potential of targeting histone modifications and specific non-coding RNAs as novel therapeutic strategies.

Functional Genomics and Pathogenesis

Functional genomic studies have pinpointed key pathways involved in psoriasis pathogenesis. The IL-23/Th17 axis takes center stage, with specific gene variants linked to both susceptibility and disease severity. Research has also shown that patients with particular variations in the IL23R gene respond more favorably to IL-23 inhibitors.

Beyond the immune system, functional genomics has revealed the role of skin barrier dysfunction in psoriasis. Mutations in genes responsible for maintaining a healthy skin barrier can increase susceptibility to environmental triggers and worsen disease.

Similarly, variations in genes involved in innate immune activation pathways contribute to disease initiation. And a recent study identified that a novel mutation in CARD14 was associated with particularly severe psoriasis, highlighting the importance of understanding these pathways for targeted therapies.

Proteomic Insights

Proteomic research, which is the study of protein profiles, provides valuable insights complementary to genetic findings. Large-scale analyses have identified panels of proteins that can accurately predict disease activity and treatment response.

Furthermore, researchers have discovered dysregulated proteins involved in oxidative stress and lipid metabolism pathways in psoriatic skin, potentially opening doors to new therapeutic targets. Excitingly, proteomic profiling might even predict an individual's response to specific medications, paving the way for truly personalized treatment plans.

Clinical Implications and Future Directions

As our understanding of psoriasis genetics evolves, so does the potential for more targeted screening and risk stratification approaches. For example, it’s been reported that individuals in the highest polygenic risk scores (PRS) quintile had a 5.8-fold increased risk of developing psoriasis compared to the lowest quintile, allowing for early intervention in high-risk individuals.

Through pharmacogenomic and pharmacogenetic studies, advancements toward precision medicine to guide therapeutic interventions are possible. For instance, a study found that patients with the HLA-C*06:02 allele responded better to ustekinumab than to adalimumab.

Additional studies predicting and monitoring responses to treatment are advantageous to personalize treatment plans.

What’s more is that the rapid evolution of genomics and genetics in psoriasis continues to uncover novel treatment targets, such as topical histone deacetylase inhibitors in mild-to-moderate psoriasis. Additionally, understanding the shared genetic loci between psoriasis and its comorbidities, such as psoriatic arthritis, could lead to strategies for early intervention and improved management of these conditions.

Psoriasis, like other diseases with multifaceted etiologies, remains a challenge. Incomplete understanding of gene-environment interactions, the polygenic nature of the disease, and the role of epigenetics make it difficult to accurately predict psoriasis solely based on genetic data. Ethical considerations regarding potential discrimination based on genetic predisposition also need careful consideration.

However, integration of genetic, epigenetic, and proteomic data is revolutionizing our approach to psoriasis management. While routine molecular profiling is not yet standard, consideration of these molecular findings when evaluating and treating patients will likely be an essential tool in our practice. By leveraging these multifaceted insights, patient care can significantly be impacted through the optimization of our approach to screening and risk stratification, personalized treatment selection, novel therapeutic targets, and comorbidity management.

References:

Al-Sofi RF, Bergmann MS, Nielsen CH, Andersen V, Skov L, Loft N. The association between genetics and response to treatment with biologics in patients with psoriasis, psoriatic arthritis, rheumatoid arthritis, and inflammatory bowel diseases: A systematic review and meta-analysis. Int J Mol Sci. 2024;25(11). doi:10.3390/ijms25115793

Dand N, Stuart PE, Bowes J, et al. GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets. medRxiv. Published online October 5, 2023. doi:10.1101/2023.10.04.23296543

Guo J, Zhang H, Lin W, Lu L, Su J, Chen X. Signaling pathways and targeted therapies for psoriasis. Signal Transduct Target Ther. 2023;8(1):437. doi:10.1038/s41392-023-01655-6

Leotsakos G, Katafigiotis I, Leotsakos I, et al. Proteomics in psoriasis: Recent Advances. In Vivo (Brooklyn). 2024;38(3):1000-1008. doi:10.21873/invivo.13533

Mateu-Arrom L, Puig L. Choosing the right biologic treatment for moderate-to-severe plaque psoriasis: the impact of comorbidities. Expert Rev Clin Pharmacol. 2024;17(4):363-379. doi:10.1080/17512433.2024.2340552

Olafsson S, Rodriguez E, Lawson ARJ, et al. Effects of psoriasis and psoralen exposure on the somatic mutation landscape of the skin. Nat Genet. 2023;55(11):1892-1900. doi:10.1038/s41588-023-01545-1

Olejnik-Wojciechowska J, Boboryko D, Bratborska AW, et al. The role of epigenetic factors in the pathogenesis of psoriasis. Int J Mol Sci. 2024;25(7):3831. doi:10.3390/ijms25073831

Shellard EM, Rane SS, Eyre S, Warren RB. Functional genomics and insights into the pathogenesis and treatment of psoriasis. Biomolecules. 2024;14(5):548. doi:10.3390/biom14050548