Using genomics and functional biology to understand fibrinogen and factor XIII and their effects on thrombotic diseases

PROJECT SUMMARY Fibrinogen and factor XIII (FXIII) are essential components of the blood coagulation cascade and major determinants of both bleeding and clotting. Most fibrinogen circulates as a heterohexamer containing 2 γA chains (Aa2Bβ2γ2); however, ~8-15% of circulating fibrinogen contains an alternatively spliced γ' chain that has unique anticoagulant properties. Plasma FXIII circulates as a heterotetramer (A2B2) bound to the fibrinogen γA chain. Conversion of fibrinogen to a fibrin network and subsequent crosslinking of the network by activated FXIII (FXIIIa) is essential for fibrin structural and biochemical stability. Consequently, these proteins are essential for hemostasis and have also been implicated in thrombotic diseases. Our previous genome-wide association studies identified loci for total fibrinogen and γ' fibrinogen, and we explored the relationship between genetically determined levels of these proteins and several arterial and venous thrombotic diseases. However, these studies were largely limited to European populations and did not directly disentangle the complex and competing effects of γA versus γ' fibrinogen isoforms. Moreover, no genome-wide studies have been conducted for FXIIIa activity despite intriguing data linking FXIII, and its ability to crosslink fibrin, with hemostasis and thrombosis. Thus, despite advances, knowledge gaps remain in understanding the genetic determinants of total and γ' fibrinogen and FXIIIa, and their relation to clinical outcomes, especially in diverse population groups. The goal of this renewal application is to leverage our multidisciplinary expertise in genomic studies and functional biology to generate new knowledge about the regulation of these coagulation factors and their relationship with thrombotic diseases. We will identify genomic contributions to total and γ' fibrinogen and FXIIIa, functionally characterize genes associated with these proteins, and conduct Mendelian Randomization studies incorporating these new loci to reveal whether genetically determined levels of total fibrinogen, alternatively spliced fibrinogen γ' chain, and FXIII affect have independent or coordinated effects on thrombotic disease risk. Successful completion of the proposed aims will advance fundamental knowledge about these essential coagulation proteins and aid in identifying new biomarkers and potential therapeutic targets for hemostasis and thrombosis.