Polygenic risk score (PRS) may be used to identify venous thromboembolism (VTE) risk in women using oral contraceptives (OCs), according to a recent study published in the American Journal of Obstetrics & Gynecology.
Takeaways
- Polygenic risk scores (PRS) can help identify venous thromboembolism (VTE) risk in women using oral contraceptives (OCs) based on a recent study in the American Journal of Obstetrics & Gynecology.
- OC use is associated with an increased risk of VTE due to excess estrogenicity, and it raises the VTE risk in women by 3 to 5 times.
- VTE is a hereditary disease with about 50% heritability, but only 6% of the risk can be attributed to known genetic factors. This suggests that there may be significant contributions from polygenic factors.
- In a study using data from the UK Biobank, women with higher PRS scores showed an increased risk of VTE when using OCs, suggesting that genetic factors may play a role in VTE risk not accounted for by traditional clinical and genetic factors.
- The study also found that the first two years of OC use were associated with a higher VTE risk, especially in women with lower PRS scores. This indicates that genetic variants may influence VTE risk, especially during the initial years of OC use.
While women manage fertility using OCs, data has found increased thrombotic event risk associated with OC use. VTE risk is also increased by OCs because of their excess estrogenicity.
Approximately 22,000 VTE events are reported in Europe per year, with VTEs being a leading cause of death worldwide. Factors other than OC use which influence VTE include factor V Leiden (FVL) and prothrombin factor II (PTM) variants. OC use increases VTE risk by 3 to 5 times in women.
The heritability of VTE is approximately 50%, but only 6% can be explained by known genetic variation. VTE has been established as a polygenic disease, but there is little data evaluating polygenic risk among OC users.
To estimate the risk of VTE among OC users through PRSs, investigators evaluated data from the UK Biobank (UKB), a population-based cohort study including over 500,000 individuals aged 37 to 72 years recruited between 2006 and 2010. Baseline characteristics were recorded at baseline, and almost all patients received genotyping.
OC-associated VTE risk among female participants was evaluated in the current analysis. VTE was reported as a binary outcome and assessed based on women’s exposure to OCs. Exclusion criteria included having missing OC use data, no data of the covariates used, not being genotyped, and not being White European.
Participants were followed from birth to either VTE diagnosis, end of follow-up, bilateral oophorectomy or hysterectomy, or menopause. The study population was stratified into 10 deciles based on PRS score or FVL and PTM carrier status.
OC use was measured during the initial assessment visit, with relevant information including ever taken OC pill, age started OC pill, and age when an OC pill was last used. Medical history and linkage to hospital admission data were used to determine the initial VTE occurrence.
The UKB Axiom array (ThermoFisher Scientific, Santa Clara, CA) and the UK BiLEVE array were used to genotype UKB participants. Instantaneous VTE risk during OC use was calculated using cox regression analyses.
There were 244,420 women included in the analyses, 10,856 of which experienced a VTE event and 193,371 of which began using OCs during follow-up. A larger number of women in the neveruser group reported a VTE event, but this is likely because these women were older at the time of recruitment, increasing the likelihood of a VTE diagnosis.
Carrying FVL was reported in 8682 OC users and carrying PTM in 4119. FVL had a frequency of 4.48% among OC users and 4.51% among never users. For PTM, these rates were 2.13% and 2.20%, respectively.
There were 24,291 women in the highest PRS category, 10,985 carrying FVL, and 5244 carrying PTM. In a base plus PRS model, PRS increased the prediction in the area under the curve by 3.5%. This indicates a higher risk of VTE among patients in higher PRS deciles.
The first 2 years of OC use were associated with increased VTE risk, but this association was not found in following years. A significantly greater effect of this interaction was found among women in the first decile vs those in the tenth decile.
These results indicated risks of VTE among OC use may be reported by genetic variants when not caught by traditional clinical and genetic factors. Investigators recommended further studies in other populations and ancestries be conducted to confirm these findings.
Reference
Lo Faro V, Johansson T, Johansson A. The risk of venous thromboembolism in oral contraceptive users: the role of genetic factors—a prospective cohort study of 240,000 women in the UK Biobank. American Journal of Obstetrics & Gynecology. 2023. doi:10.1016/j.ajog.2023.09.012
