Genetic variation and natural anticoagulants

Thesis (Master's)--University of Washington, 2020Protein C (PC), protein S (PS) and antithrombin (AT) belong to the main anticoagulant pathways that regulate hemostasis and further affect the risk of thrombotic events. Previous epidemiological studies of circulating levels of PC, PS and AT, genetic variation, and risk of venous thromboembolism (VTE) have been limited by small sample sizes and restriction to specific candidate genes only. Utilizing summary results from nine genome-wide association studies (GWAS), we conducted transethnic meta-analyses on AT, PC, and free and total PS. We identified potential novel genome-wide significant signals for AT close to the GCKR, SNX17 and BAZ1B genes in both European ancestry based analysis and transethnic analysis (Transethnic P-value = 4.41e-16, 1.45e-15, 4.01e-09, respectively), but these associations were not observed in African population in our cohorts (P-value = 0.35, 0.55, 0.36, respectively). Signals at GCKR presented significant heterogeneity between ancestries (P-value = 0.017). Also, a genome-wide signal on AT in African American population was found close to the HP gene (Transethnic P-value = 4.37e-26) but was not significant in the European ancestry population (P-value = 0.02). Another novel genome-wide association signal was found close to the ORM1 gene in relation with PS (PS free P-value = 1.16e-19, PS total P-value = 1.03e-15), suggesting possible regulatory mechanisms for PS. We also found a potential genome-wide signal (Transethnic p-value =3.73e-24) at SNX17 for PC, which is in high linkage disequilibrium (LD) with variants in GCKR. Confirmation of these potential novel associations require further analysis in independent populations

Perturbation Theory-Based Whole-Core Eigenvalue Sensitivity and Uncertainty (SU) Analysis via a 2D/1D Transport Code

For nuclear reactor physics, uncertainties in the multigroup cross sections inevitably exist, and these uncertainties are considered as the most significant uncertainty source. Based on the home-developed 3D high-fidelity neutron transport code HNET, the perturbation theory was used to directly calculate the sensitivity coefficient of keff to the multigroup cross sections, and a reasonable relative covariance matrix with a specific energy group structure was generated directly from the evaluated covariance data by using the transforming method. Then, the “Sandwich Rule” was applied to quantify the uncertainty of keff. Based on these methods, a new SU module in HNET was developed to directly quantify the keff uncertainty with one-step deterministic transport methods. To verify the accuracy of the sensitivity and uncertainty analysis of HNET, an infinite-medium problem and the 2D pin-cell problem were used to perform SU analysis, and the numerical results demonstrate that acceptable accuracy of sensitivity and uncertainty analysis of the HNET are achievable. Finally, keff SU analysis of a 3D minicore was analyzed by using the HNET, and some important conclusions were also drawn from the numerical results

Arterioscler Thromb Vasc Biol

BACKGROUND: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. METHODS: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of AT included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. RESULTS: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. CONCLUSIONS: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels