Oral postmenopausal hormone therapy and genetic risk on venous thromboembolism: gene-hormone interaction results from a large prospective cohort study

OBJECTIVE: Oral postmenopausal hormone therapy (HT) has been shown to be associated with venous thromboembolism (VTE), but whether this association is modified by VTE-associated genetic susceptibility is unknown. We examined interactions between oral HT use and a genetic risk score (GRS) of VTE. METHOD: Eligible women were postmenopausal women who had data on oral HT use, VTE incidence between 1990 and 2012, and genetic data in the Nurses’ Health Study. We built a GRS aggregating 16 VTE-related genetic variants. We used Cox regression to estimate associations of HT use with incident VTE and assessed interactions between HT use and VTE GRS. We also estimated incidence of VTE between age 50 and 79 years for groups of women defined by HT use and VTE GRS. RESULTS: We identified 432 incident VTE cases. Current HT users were at higher risk of VTE than never users (HR: 1.9, 95% CI: 1.5–2.6), with slightly higher risk for estrogen plus progestin HT than estrogen only (HR: 2.4 versus 1.9). The GRS was associated with VTE risk (HR comparing 4(th) quartile to 1(st): 2.0, 95% CI: 1.2–3.4). We did not observe significant multiplicative interactions between HT use and GRS. The estimated VTE risk difference (per 10,000 person-years) comparing 50-year-old current HT users to never users was 22.5 for women in the highest GRS quartile and 9.8 for women in the lowest GRS quartile. CONCLUSION: The VTE GRS might inform clinical guidance regarding the balance of risks and benefits of HT use, especially among younger women.