Sex Hormone-Binding Globulin and Risk of Coronary Heart Disease in Men and Women

Abstract

Background The role of sex hormone-binding globulin (SHBG) levels in clinical risk stratification and intervention for coronary heart disease (CHD) remains uncertain. We aimed to examine whether circulating levels of SHBG are predictive of CHD risk in men and women. Methods We investigated the association between SHBG and the risk of incident CHD in 128 322 men and 135 103 women free of CHD at baseline in the prospective United Kingdom Biobank (UKB) cohort. The unconfounded associations were estimated using Mendelian randomization (MR) analysis. We further conducted a meta-analysis to integrate currently available prospective evidence. CHD events included nonfatal and fatal myocardial infarction and coronary revascularization. Results In the UKB, during a median of 11.7 follow-up years, 10 405 men and 4512 women developed CHD. Serum levels of SHBG were monotonically associated with a decreased risk of CHD in both men (adjusted hazard ratio [HR] per log nmol/L increase in SHBG: 0.88 [0.83–0.94]) and women (HR: 0.89 [0.83–0.96]). MR-based analyses suggested causality and a dose-response relationship of SHBG with CHD risk. A cumulative meta-analysis including 216 417 men and 138 282 women from 11 studies showed that higher levels of SHBG were prospectively associated with decreased CHD risk in men comparing the highest with the lowest quartile: pooled relative risk (RR) 0.81 (0.74–0.89) and women (pooled RR: 0.86 [0.78–0.94]). Conclusions Higher circulating SHBG levels were directly and independently predictive of lower CHD risk in both men and women. The utility of SHBG for CHD risk stratification and prediction warrants further study.

Blood lipid levels mediating the effects of sex hormone-binding globulin on coronary heart disease: Mendelian randomization and mediation analysis

“…A meta-analysis incorporating ten previous observational studies indicates that circulating SHBG levels are associated with lower CHD risk in both men and women 10 . Furthermore, the results of two recent MR studies on the same topic also support the conclusion that an increase in SHBG levels is associated with a reduced risk of CHD 10 , 44 . Our mediation analysis highlights that this biological effect of SHBG is largely achieved by improving the blood lipid profiles.…”

“…Therefore, these findings need to be further verified by evidence-based medicine methods with higher level of evidence. Additionally, other studies have shown inverse association between serum SHBG levels and the risk of coronary heart disease (CHD) 10 , but the mechanism is not clear. The lipid infiltration hypothesis is currently the most widely accepted theory explaining the mechanism of atherosclerosis 11 .…”

A protective role of genetically predicted sex hormone-binding globulin on stroke

“…Different levels of endogenous sex hormones may partially explain the difference. In postmenopausal women, the lack of protective sex hormones may lead to an increased risk of stroke [ 9 , 12 , [20] , [21] , [22] , [23] , 26 , [35] , [36] , [37] , [38] , [39] ]. In this study, our findings demonstrate that SHBG exerts a protective effect on stroke and IS [ 12 , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] ].…”

Healthy lifestyle linked to innate immunity and lipoprotein metabolism: a cross-sectional comparison using untargeted proteomics

“…SHBG is negatively related to adiposity and serum glucose and insulin, but the relationship to inflammation has not yet been clearly established 36 . Low SHBG is a risk factor for type 2 diabetes and cardiovascular disease 41 , 42 . Thus, high SHBG combined with other proteins that were elevated in the LIFE group such as adiponectin (ADIPOQ), apolipoproteins A-1, M, C-1, and D, and alpha-2-macroglobulin (A2M) are consistent with a proteomic profile linked to lowered chronic disease risk 39 , 41 , 42 .…”