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CME Evaluation

Oral Communication Session

Venous Thromboembolism

Session: VTE risk factors

OC 54.1 - `Genome-Wide Investigation of Exogenous Female Hormones, Genetic Variation, and Venous Thromboembolism Risk: the INVENT Consortium

Tuesday, June 25, 2024
09:30 – 09:45 ICT
Room: Ballroom B4
Background: Increased risk of venous thromboembolism (VTE) is a life-threatening side effect for users of oral contraceptives (OCs) or hormone therapy (HT).

Aims: To investigate the potential for genetic predisposition to VTE in OC or HT users, we conducted a gene-by-environment (GxE) case-only meta-analysis.

Methods: Use or non-use of OCs (7 studies) or HT (8 studies) at the time of the VTE event was determined by pharmacy records or self-report. A synergy index (SI) was modeled for each variant in each study and estimated supra-multiplicative GxE interaction. SI parameters were first meta-analyzed across OC and HT studies, and subsequently meta-analyzed to obtain an overall estimate. Primary analysis was agnostic and interrogated all imputed genotypes using p-value threshold of < 5.0x10-8; secondary analyses were candidate-based. We also conducted GxE analyses using a polygenetic risk score derived from a large VTE genome-wide association study.

Results: VTE case-only OC meta-analysis included 2,895 OC users and 6,607 non-users; case-only HT meta-analysis included 2,434 HT users and 12,793 non-users. In primary analyses, no variant reached genome-wide significance, but the smallest p-value approached statistical significance: rs9386463 (p = 5.03x10-8). We tested associations for 138 candidate variants and identified 2 exceeding statistical significance (0.05/138=3.62x10-4): F5 rs6025 (p = 1.87x10-5, SI = 1.29; previously observed) and F11 rs2036914 (p = 2.0x10-4, SI = 0.91; new observation). In preliminary analyses, GxE VTE-derived PRS contributed to a GxE interaction more strongly among users/non-users of OC (SI = 1.66; 95% CI 1.22 - 2.25) than users/non-users of HT (SI = 1.07; 95% CI: 0.99-1.14); among the former, the association was mostly explained by the F5 rs6025 and by F2 rs1799963 variants.

Conclusion(s): The candidate-variant approach to identify supra-multiplicative associations between genetic variation and OC-HT use in VTE identified a new association with common genetic variation in F11 while the agnostic interrogations did not yield new discoveries.