Genetically mimicked effects of evinacumab on psoriasis: a drug target Mendelian randomization study.

Summary

Two-sample Mendelian randomization using large GWAS datasets indicates that genetically higher triglycerides and LDL-C increase psoriasis risk and that genetically mimicked ANGPTL3 inhibition (as with evinacumab) lowers risks of psoriasis and arthropathic psoriasis. These results support lipid modulation—particularly via ANGPTL3—as a potential preventive or therapeutic strategy in psoriasis.

Key Findings

• Each SD increase in triglycerides genetically increased psoriasis risk (OR 1.17; 95% CI 1.03–1.32).
• Each SD increase in LDL-C genetically increased psoriasis risk (OR 1.22; 95% CI 1.05–1.43) and was associated with arthropathic psoriasis (OR 1.30), psoriasis vulgaris (OR 1.87), and guttate psoriasis (OR 2.19).
• Genetically mimicked ANGPTL3 inhibition (evinacumab) reduced psoriasis risk (OR 0.752 per SD TG reduction) and arthropathic psoriasis risk (OR 0.266 per SD LDL-C reduction).

Clinical Implications

Supports consideration of clinical trials testing evinacumab or ANGPTL3 inhibitors for psoriasis and psoriatic arthritis prevention or control, particularly in dyslipidemic patients; encourages integrated management of lipid abnormalities in psoriasis.

Limitations

• MR assumptions (e.g., no horizontal pleiotropy) may be violated and cannot be fully tested.
• Findings reflect lifelong genetic exposure; translatability to short-term pharmacologic intervention remains uncertain and ancestry is largely European.

Future Directions

Conduct randomized or adaptive trials of evinacumab in psoriasis/psoriatic arthritis, investigate ANGPTL3’s immunodermatologic mechanisms, and assess benefit–risk in dyslipidemic phenotypes.