Date of Award

Spring 5-2019

Degree Name

Master of Public Health (MPH)

Advisor(s)

CATHERINE TROISI, PHD

Second Advisor

PAUL DE VRIES, PHD

Abstract

Introduction: Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ′) fibrinogen is an isoform of fibrinogen and has anticoagulant properties, including inhibiting thrombin and slowing platelet aggregation, that may affect clot formation.

Methods: Two-sample Mendelian randomization (MR) was applied to estimate the causal effect of total circulating fibrinogen and its isoform, γ′ fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from published genome-wide association studies of fibrinogen, VTE, and ischemic stroke, and an unpublished study of γ′ fibrinogen. Genetic instruments for γ′ fibrinogen and total fibrinogen were selected by pruning genome wide significant variants to linkage disequilibrium r2 < 0.1. The inverse variance weighted MR approach was used to estimate effects in the main analysis, with additional approaches that are more robust to the inclusion of pleiotropic variants applied in sensitivity analyses, including MR-Egger, weighted median MR, and weighted mode MR.

Results: The main inverse variance weighted MR estimates (Figure 1) based on 16 genetic instruments for γ′ fibrinogen and 75 genetic instruments for total fibrinogen (Figure 2) indicated a protective effect of both γ′ fibrinogen and total fibrinogen on VTE risk. Higher γ′ fibrinogen levels decreased the risk of cardioembolic and large artery stroke. Higher total fibrinogen levels decreased the risk of cardioembolic stroke but increased the risk of large artery and small vessel stroke. Effect estimates were consistent across sensitivity analyses, indicating that the results are unlikely to be attributable to the inclusion of pleiotropic variants.

Conclusion: Our results are consistent with effects of genetically determined γ′ fibrinogen on VTE and ischemic stroke. The strong inverse association found between γ′ fibrinogen and VTE and ischemic stroke subtypes suggests the need to evaluate γ′ fibrinogen’s causal effect on other cardiovascular outcomes. Further research is needed to explain the protective effects seen in total fibrinogen on VTE and on cardioembolic stroke.

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