Joint association between endogenous sex hormones, genetic risk factors, and incident venous thromboembolism in women

Venous thromboembolism (VTE) is associated with genetic variations and the use of exogenous hormones such as oral contraceptives and hormone therapy. Previous studies have shown an inconsistent association between endogenous hormone concentrations and markers of coagulation and fibrinolysis, known risk factors of VTE. Further, little is known about the joint effects of genetic and endogenous risk factors. Using a nested case-control study design within the UK Biobank Cohort, we studied associations of endogenous hormone (estradiol, free testosterone, and SHBG) concentrations and genetic risk scores (GRS based on previously characterized VTE susceptibility variants in 37 genes) with risk of incident VTE among 661 premenopausal and 4,231 postmenopausal women (VTE cases n=126 and n=939 in pre- and postmenopausal women, respectively). We fit logistic regression models, examining the outcome of VTE by endogenous hormone concentrations, adjusting for age at assessment, BMI, diabetes diagnosis, cancer diagnosis, smoking status, and assessment site. We also evaluated the interaction of genetic risk scores and endogenous hormone concentrations with VTE incidence using and interaction term and log likelihood test, adjusting our models as previously specified. Higher endogenous SHBG concentrations were associated with a greater risk of VTE incidence, [(OR= 1.13 (95 % CI: 1.00, 1.43) per 30 nmol/L increment of SHBG; p = 0.27) in premenopausal women; OR= 1.13 (95 % CI: 1.00, 4 1.34) per 30 nmol/L increment of SHBG; p = 0.02) in postmenopausal women]. There was no evidence of associations of VTE incidence with free testosterone or estradiol concentrations. A Genetic Risk Score (GRS) based on 37 known VTE susceptibility variants was associated with increased VTE risk [OR= 2.03 (95% CI: 1.62, 2.60), p = 3.31 x 10-9 among premenopausal women; OR = 1.65 ( 95% CI: 1.51, 1.79), p< 2.0 x 10-16 among postmenopausal women].There did not appear to be a significant interaction between endogenous hormone concentrations and GRS with incident VTE risk [GRS and Testosterone interaction: OR = 0.954 ( 0.83, 1.11), p = 0.53 overall; GRS and SHBG interaction: OR = 1.001 (0.998, 1.004), p = 0.52 overall; GRS and detectible Estradiol: OR= 1.13 (0.88, 1.46), p = 0.34 overall]. Our findings of significant associations of SHBG concentration and GRS with VTE risk is consistent with existing literature.