Shared Genetic Risk Factors for Multiple Sclerosis and Psoriasis: Unveiling the Molecular Link

In a study published in the Annals of Neurology in 2023, researchers led by Matthew T. Patrick, PhD, and colleagues have unveiled shared genetic risk factors between multiple sclerosis (MS) and psoriasis, two complex immune-mediated diseases. By integrating epidemiological data and genetic analyses, the study provides compelling evidence for the involvement of interleukin-17 (IL-17) and Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling in the pathogenesis of both diseases.

Epidemiology and Genetic Overlap
The study leveraged medical claims data from over 30 million patients, including 141,544 with MS and 742,919 with psoriasis. Logistic regression analyses revealed that psoriatic patients have a significantly higher risk of developing MS (odds ratio [OR] 1.07, p = 1.2 × 10^-5) after controlling for potential confounders. This epidemiological link is supported by genetic data from genome-wide association studies (GWAS), which included 11,024 psoriatic and 14,802 MS cases, along with 43,039 controls.

Trans-Disease Meta-Analysis and Shared Genetic Loci
To identify shared genetic factors, the researchers performed a trans-disease meta-analysis (TDMA), revealing over 20 shared and opposing genetic loci outside the major histocompatibility complex (MHC). These loci showed significant genetic colocalization, indicating that the same genetic variants influence the risk of both diseases. Notable shared loci include genes such as TNFAIP3, TYK2, and TNFRSF1A, which are involved in IL-17 and tumor necrosis factor-alpha (TNF-α).

IL-17 and JAK-STAT Signaling
The co-expression analysis of genes from shared loci identified distinct clusters enriched in with IL-17/TNF-α and JAK-STAT signaling. These play crucial roles in immune regulation and inflammation. For instance, TNFAIP3 and TYK2 are key regulators in the TNF-α and JAK-STAT signaling, respectively. The enrichment of these highlights their importance in the molecular mechanisms underlying both MS and psoriasis.

Mendelian Randomization and Causal Relationships
Mendelian randomization (MR) analysis further established a significant causal effect of psoriasis on MS (OR 1.04, p = 5.8 × 10^-3), independent of other autoimmune conditions such as type 1 and type 2 diabetes, inflammatory bowel disease, and vitamin D levels. This finding underscores the importance of considering psoriasis as a risk factor for MS and provides a basis for future studies to explore therapeutic interventions targeting shared molecular signalings.

Implications for Treatment and Precision Medicine
The identification of shared genetic risk factors and molecular cascades between MS and psoriasis opens new avenues for precision medicine. Understanding the common etiology and pathophysiology of these diseases can lead to the development of targeted therapies that modulate IL-17 and JAK-STAT signaling. For example, IL-17-regulating drugs like secukinumab and JAK inhibitors could potentially benefit patients suffering from both conditions.

In summary, this study provides a comprehensive understanding of the genetic and molecular links between MS and psoriasis. The shared involvement of IL-17 and JAK-STAT signaling highlights the potential for novel therapeutic approaches, paving the way for improved management and treatment of these comorbid diseases.

Reference:
Patrick, M. T., Nair, R. P., He, K., Stuart, P. E., Billi, A. C., Zhou, X., ... & Tsoi, L. C. (2023). Shared Genetic Risk Factors for Multiple Sclerosis/Psoriasis Suggest Involvement of Interleukin‐17 and Janus Kinase–Signal Transducers and Activators of Transcription Signaling. Annals of Neurology, 94(2), 384-397.