Genome Med. 2026 Jul 4. doi: 10.1186/s13073-026-01709-8. Online ahead of print.
ABSTRACT
BACKGROUND: Sex hormones and HIV infection both influence cardiovascular health. However, the association 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 (IMT > 1.5 mm) using high-resolution B-mode ultrasound, and performed 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. In stratified analyses of men with (MWH) and without HIV (MWOH) and adjusting for covariates and multiple testing, we (1) examined associations of sex hormones with plaque; (2) characterized multi-omics profiles related to sex hormones; and (3) generated sex hormone-related omics scores via linear combination of related species, metabolites, and proteins, respectively, to explore whether these sex hormone-related multi-omics profiles were associated with plaque.
RESULTS: Median age of participants was 62 years (interquartile range: 58-68), and 31.5% had carotid artery plaque. Sex hormones were differentially associated with plaque in MWH and MWOH. In MWH, an inverse association was observed between SHBG and plaque (OR = 0.60 per 1-SD increase, 95% CI: 0.41, 0.90). Furthermore, higher SHBG levels were associated with overall gut microbial composition, lower abundance of species from genera Prevotella, Fibrobacter and Coprococcus, higher levels of certain metabolites (primarily lipid and carnitine metabolites) and proteins enriched in the cell-cell adhesion pathway. Some SHBG-related species (e.g., Mediterranea massiliensis), metabolites (e.g., phosphatidylcholine-based lipids) and proteins (e.g., enriched in immune response pathway) were also associated with plaque in MWH. All three SHBG-related omics scores were inter-correlated and inversely associated with plaque in MWH. 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, and related microbial species, circulating metabolites, and proteins, were inversely associated with carotid artery plaque. These findings suggested that SHBG may play a protective role in subclinical atherosclerosis in MWH.
PMID:42400043 | DOI:10.1186/s13073-026-01709-8