Unveiling new protein biomarkers and therapeutic targets for acne through integrated analysis of human plasma proteomics and genomics.

Background: The current landscape of acne therapeutics is notably lacking in targeted treatments, highlighting a critical need for the discovery of new drug targets to improve treatment outcomes.

Objectives: This study aims to investigate the connections between proteomics and genetics in relation to acne across extensive population cohorts, aspiring to identify innovative preventive and therapeutic approaches.

Methods: Employing a longitudinal cohort of 54,306 participants from the UK Biobank Pharmacological Proteomics Project (UKB-PPP), we performed an exhaustive evaluation of the associations between 2,923 serum proteins and acne risk. Initial multivariate Cox regression analyses assessed the relationship between protein expression levels and acne onset, followed by two-sample Mendelian Randomization (TSMR), Summary-data-based Mendelian Randomization (SMR), and colocalization to identify genetic correlations with potential protein targets.

Results: Within the UKB cohort, we identified 19 proteins significantly associated with the risk of acne. Subsequent analysis using Two-Sample Mendelian Randomization (TSMR) refined this to two specific proteins: FSTL1 and ANXA5. Each one-standard deviation increase in the expression levels of FSTL1 and ANXA5 was associated with a 24% and 32% increase in acne incidence, respectively. These results were further validated by additional Summary-data-based Mendelian Randomization (SMR) and differential expression analyses.

Conclusions: Our comprehensive analysis of proteomic and genetic data from a European adult cohort provides compelling causal evidence that several proteins are promising targets for novel acne treatments.