Pulmonary vascular disease & thromboembolismCross-sectional study
Population-Scale Studies of Protein S Abnormalities and Thrombosis
- Cross-sectional study
- longitudinal population cohorts
- Firth logistic regression
Authors' conclusion
True inherited loss of function in PROS1 is rare but represents a stronger risk factor for VTE in the general population than previously understood. Acquired, environmental, or trans-acting genetic factors are more likely to cause circulating protein S deficiency than coding variation in PROS1, and low plasma protein S is associated with VTE.
Study context
- Population
- UK Biobank and US All of Us population cohortsUK Biobank n = 426,436 · UK Biobank 426,436 · US All of Us 204,006
- Exposure
- Carriers of rare germline PROS1 variants vs noncarriers
- Outcome
- Thrombosis risk (VTE and arterial thrombosis) associated with PROS1 variants and low plasma protein S
Main finding
As reported in the abstract
Functional impact score (FIS) 1.0
0.0091% in the UK and 0.0178% in the US
Adjusted prevalence
FIS ≥0.7
0.22% in the UK and 0.20% in the US
Adjusted prevalence
Observational data: associations, not effects.
Further findings
| Outcome | FIS 1.0 | FIS ≥0.7 | Noncarriers | P value |
|---|---|---|---|---|
| Total plasma protein S level, FIS 1.0 carriers (proteomics subset) | 48.0% of normal | Not reported in the abstract | Not reported in the abstract | P = 0.02 |
- Total plasma protein S level, FIS 1.0 carriers (proteomics subset): n = 44 431
Arterial thrombosis (MI, PAD, noncardioembolic ischemic stroke)
- No association with coding PROS1 variants
Low plasma protein S
- PROS1 variants correlated poorly with low protein S; protein S deficiency significantly associated with venous thromboembolism (VTE) and PAD regardless of carrier status
VTE over lifetime (Kaplan-Meier), PROS1 loss of function
- Elevated VTE risk persisted throughout life
- log-rank P = .0005
Original publication
Summarised from the published abstract; every number is checked against it