TYK2 rs34536443 (P1104A) Variant Suppresses ICAM1-Mediated Inflammation: Insights From Mendelian Randomization and...

Area of Science:

• Immunology
• Genetics
• Dermatology

Background:

• Psoriasis pathogenesis involves genetic factors, including Tyrosine Kinase 2 (TYK2).
• The precise role and regulatory mechanisms of TYK2 in psoriasis are not fully understood.
• Identifying key proteins and pathways is crucial for understanding psoriasis development.

Purpose of the Study:

• To identify psoriasis-associated proteins using Summary-based Mendelian Randomization (SMR).
• To elucidate the regulatory mechanisms of identified proteins in psoriasis.
• To investigate the therapeutic potential of targeting the TYK2-ICAM1 axis.

Main Methods:

• Summary-based Mendelian Randomization (SMR) analysis integrated with pQTL data to identify psoriasis-associated proteins.
• Functional analysis of a TYK2 single nucleotide polymorphism (SNP), rs34536443 (P1104A), in THP-1 cells.
• Assessment of ICAM1 and cytokine expression following lipopolysaccharide (LPS) stimulation in mutant cells.
• Evaluation of a TYK2 inhibitor (Deucravacitinib) in an imiquimod (IMQ)-induced psoriasis mouse model.

Main Results:

• SMR analysis identified Intercellular Adhesion Molecule 1 (ICAM1) as a causal protein for psoriasis, regulated by the TYK2 SNP rs34536443.
• The TYK2-P1104A mutation significantly reduced LPS-induced ICAM1 and pro-inflammatory cytokine (IL-1β, TNF-α, IL-6, IL-18) expression in THP-1 cells.
• In vivo, Deucravacitinib treatment effectively downregulated ICAM1 in an IMQ-induced psoriasis mouse model.

Conclusions:

• ICAM1 is identified as a key mediator in psoriasis, with its regulation linked to the TYK2 SNP rs34536443.
• The TYK2-P1104A variant demonstrates anti-inflammatory effects by attenuating ICAM1 and cytokine production.
• These findings highlight the TYK2-ICAM1 axis as a significant pathway in psoriasis and support TYK2 inhibitors as a potential therapeutic strategy.