Background
Sex hormones and HIV infection both influence cardiovascular health. However, the relationship between sex hormones and subclinical atherosclerosis is not fully understood, especially in the context of HIV.
Methods
Among 321 men (65% with HIV) from the MACS/WIHS Combined Cohort Study, we measured 14 serum sex hormones and sex hormone-binding globulin (SHBG), assessed carotid artery plaque using B-mode ultrasound, and performed shotgun metagenomic sequencing on stool samples. In 312 men, we measured 986 plasma metabolites via liquid chromatography-tandem mass spectrometry and 2883 plasma proteins using the Olink Explore 3072 platform. Separately in men with and without HIV (MWH, MWOH) and with adjustment for covariates, we (1) examined associations of sex hormones with plaque; (2) characterized multi-omics profiles related to sex hormones; and (3) explored whether identified multi-omics signatures mediate the relationship between sex hormones and plaque (Fig. 1a).
Results
Mean age was 63.0±7.4 years, and 31.5% had carotid artery plaque. Sex hormones were differentially associated with plaque in MWH and MWOH. In MWH, SHBG was associated with lower odds of plaque (OR=0.60, 95% CI: 0.41, 0.90), overall gut microbial composition, lower abundance of species from Prevotella, Fibrobacter and Coprococcus, higher levels of certain metabolites (mainly lipid and carnitine metabolites) and proteins enriched in the cell-cell adhesion pathway. Some SHBG-related species (e.g., Mediterranea massiliensis), metabolites (e.g., Hex2Cer 42:2;O2) and proteins (e.g., enriched in immune response) were also associated with plaque in MWH. We then generated SHBG-related microbiome, metabolite and protein scores via linear combination of related species, metabolites and proteins, respectively. All SHBG-related -omics scores were inter-correlated and inversely associated with plaque in MWH (Fig. 1b). Mediation analysis suggested that the metabolite and protein scores, but not the microbiome score, could mediate the protective association of SHBG with plaque (mediated proportions: 43.2% and 39.0%). In MWOH, estrone-sulfate was positively associated with plaque (OR=3.80, 95% CI: 1.41, 10.22) but not with any species, metabolites or proteins.
Conclusions
Higher SHBG was associated with lower odds of carotid artery plaque in MWH, possibly explained by alterations in lipid metabolites and proteins involved in immune response and cell function regulation. SHBG may play a protective role in cardiovascular disease in MWH.