Exploring sex-specific causal links between thousands of proteins and lipid metabolism using the UK Biobank Pharma Proteomics Project data

Lipid traits are known to be sex-differential, but the underlying molecular players are largely unknown. Herein, we aim to highlight differential molecular signatures in lipid metabolism between males and females by identifying proteins that are causally linked to lipids in a sex-specific or sex-differentiated manner. Since protein levels are downstream products of gene expression, proteomics data can be crucial to understand etiology of sex-differences in lipids metabolism.We used sex-specific pQTL summary statistics for 2,923 circulating proteins measured in the UK Biobank Pharma Proteomics Project, along with sex-specific summary statistics of lipids from the Global Lipids Genetics Consortium. We combined these using two-sample Mendelian Randomization analyses and applied stringent multiple testing p-values correction and sensitivity analyses.We identified several sex-specific significant causal links between protein levels and lipid phenotypes: 83 were exclusive to females and 82 to males, 46% of which would not have been identified using combined-sex GWASs. The estimated causal effect was instead significant in both sexes but substantially different in size for 39 causal relationships (p < 0.05). Intriguingly, several of these proteins were previously shown to be involved in inflammation and cardiometabolic diseases, such as Apolipoprotein(a) and lipoprotein lipase. Furthermore, two sex-specific proteins - LEPR and LPA - are molecular targets of emerging cardiometabolic therapies, highlighting the need for future investigations to determine whether these protein-level differences translate into sex-specific efficacy or safety in clinical trials and routine treatments.The discovery of these sex-differences can provide important etiological insights into the management of lipid metabolism. Such knowledge may in turn improve the predictive use of sex-specific pQTLs and point to new therapeutic gender specific strategies to prevent cardiovascular disease.