Sex hormone‐binding globulin levels are not causally related to venous thrombosis risk in women not using hormonal contraceptives

Summary. Background: Oral contraceptive use increases the risk of venous thrombosis as well as sex hormone‐binding globulin (SHBG) levels. Furthermore, increased SHBG levels are positively associated with activated protein C (APC) resistance and thrombotic risk in oral contraceptive users. Objectives: To determine whether increased SHBG levels are causally related to venous thrombosis in women not using hormonal contraceptives. Methods: Premenopausal women were selected from a case–control study on venous thrombosis, the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study (23 patients; 258 controls). Women using hormonal contraceptives were excluded. First, the risk of venous thrombosis with SHBG levels above the normal reference range (70 nm) was determined. Second, because multiple regulatory factors affect SHBG levels and residual confounding may remain, we determined six single‐nucleotide polymorphisms (SNPs) in the SHBG gene and assessed the risk of venous thrombosis in a different case–control study, the Leiden Thrombophilia Study (LETS) (20 patients; 74 controls), and in the MEGA study. Finally, the association between SHBG levels and the normalized activated partial thromboplastin time‐based APC resistance (an intermediate endpoint for venous thrombosis) was determined. Results: Elevated SHBG levels (> 70.0 nm) were associated with venous thrombosis (odds ratio 1.92; 95% confidence interval [CI] 0.74–5.00). However, this finding can be explained by residual confounding. Two SNPs in the SHBG gene affected SHBG levels, but not venous thrombosis risk. Furthermore, SHBG levels in controls were not associated with APC resistance (SHBG level, > 70.0 vs. ≤ 70.0 nm: mean difference in normalized APC sensitivity ratio, 0.03; 95% CI −0.05 to 0.10). Exclusion of women with FV Leiden did not materially change these results. Conclusions: Increased SHBG levels are not causally related to the risk of venous thrombosis.