Exploring Genetic Drug Targets in Acne Vulgaris: A Comprehensive Proteome-Wide Mendelian Randomization Study.

BACKGROUND Acne vulgaris presents a substantial clinical challenge due to its complex pathophysiology and significant impact on quality of life. Identification of novel therapeutic targets for acne using genetic tools can guide the development of more effective treatments. METHODS Utilizing a dataset comprising 35 559 Icelandic individuals, we performed proteomic analyses to quantify 4709 circulating proteins. We integrated these data with acne-specific genome-wide association studies (GWAS) encompassing 34 422 acne patients and 364 991 controls. Mendelian randomization (MR) analyses employed the TwoSampleMR tool and Summary-data-based Mendelian Randomization (SMR) to estimate the causal effects of identified proteins on acne risk. Colocalization analyses assessed the likelihood of shared genetic etiology between protein levels and acne using the "coloc" R package. RESULTS Our proteome-wide MR analysis initially identified 128 proteins potentially associated with acne risk. Following multiple testing corrections using the Benjamini-Hochberg method, fatty acid synthase (FASN) and tissue inhibitor of metalloproteinases 4 (TIMP4) remained significantly associated with acne risk. FASN exhibited a protective effect against acne (OR = 0.768, 95% CI: 0.676-0.872, p = 4.685E-05), while TIMP4 was associated with an increased risk (OR = 1.169, 95% CI: 1.103-1.241, p = 1.956E-07). Colocalization analysis supported a shared genetic basis for these protein-acne associations, with posterior probabilities indicating strong evidence of shared causal variants. CONCLUSION Our findings highlight the utility of integrative genomic approaches in identifying potential therapeutic targets for acne. FASN and TIMP4, in particular, demonstrate strong potential as targets for therapeutic intervention, pending further validation through clinical research. These results offer a foundation for targeted acne treatment development, aligning with personalized medicine principles.