Proteome variation is associated with reproductive health, disease risk, and immune function, and is influenced by genetic and environmental factors. Sex is a major overall contributor to variation in the plasma proteome (Sun et al., Nature 2023; Eljarn et al., Nature 2023; Carrasco-Zanini et a., Nature Metabolism 2024), however it is difficult to decouple the role of genetics and sex hormones.
In this project we generated Olink ExploreHT data in a longitudinal adult cohort of feminizing Gender-Affirming Hormone Therapy (GAHT) at baseline and 6 months following combined estrogen and anti-androgen treatment. We measured 5,329 proteins in the plasma before and after extensive changes in circulating estrogen and testosterone concentrations, allowing us to specifically study how sex hormones influence the plasma proteome.
Using the supplemental data from the UK Biobank Pharma Proteomics Project of 45,000 individuals (Sun, Nature 2023) we found that 63 out of the top 100, including 8 out of the top 10, proteins identified as sex-specific in Olink data in the UK Biobank were changed by 6 months of GAHT. This suggests that 6 month of GAHT can account for much of the sex-specific protein differences.
Now, we are applying for access to the Olink data from the UK Biobank Pharma Proteomics Project to ask further questions about the role of sex and age on proteins in the circulation. Specifically, we plan to explore how GAHT-associated proteins are influenced by estradiol and testosterone concentrations in participants in the UK Biobank, and how menopause and hormone replacement therapy influences their concentrations.
Our overall aim is to decouple sex and genetics to understand the proportion of the sex-differences in protein expression that are attributable to sex hormone concentrations.