LAUSR

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.