Sex differences in cholesterol metabolism and their association with SCORE2 cardiovascular risk based on cholesterol homeostasis markers and principal component analysis

Abstract Background Sex‐related differences in cholesterol metabolism may influence cardiovascular disease risk and outcomes. Understanding these differences in the context of SCORE2 predicted cardiovascular risk could support the implementation of sex‐specific prevention and therapeutic protocols. Methods In this cross‐sectional study, serum levels of non‐cholesterol sterols, desmosterol, lathosterol (markers of cholesterol synthesis) and campesterol and β‐sitosterol (markers of cholesterol absorption) were analysed in 100 healthy adults (50 men, 50 women). CVD risk was assessed with SCORE2. Principal component analysis (PCA) was used to identify latent structures linking cholesterol homeostasis to sex and cardiovascular risk. K‐means clustering and linear regression were used to examine sex‐specific and SCORE2‐related patterns. Results Men had significantly higher cholesterol synthesis markers, while women had higher cholesterol absorption markers. The desmosterol/lathosterol ratio was significantly higher in women, indicating preferential utilization of the Bloch biosynthetic pathway. PCA revealed three principal components (PCs), with PC1 distinguishing sex ( p < .0001) and PC2 correlating with SCORE2 risk category ( p < .0001). Cluster analysis based on PC1 and PC2 revealed two groups that correlated strongly with biological sex ( χ 2 = 18.7, p < .0001). Elevated synthesis and absorption markers were associated with a higher risk according to SCORE2, especially in women. Conclusions Our results showed higher cholesterol synthesis in men and higher cholesterol absorption in women. PC1 reflected sex‐specific differences, while PC2 was sex‐independent but SCORE2‐dependent. D/L, L, K, B, which contributed to PC3, accounted for a substantial proportion of the variance encompassing both sex and SCORE2 risk. These findings suggest differences in cholesterol metabolism between sexes, with possible implications for future CVD risk management.