Refining the roles of genetic, environmental, and endogenous factors in Factor VIII activity levels. Público
Viel, Kevin Roland (2007)
Abstract
Background: Factor VIII (FVIII) is a central coagulation protein associated with hemophilia A at one end of the bleeding spectrum and thrombosis at the other end. A wide variety of factors are associated with increases in its activity, such as von Willebrand factor (VWF), exertion, mental stress, inflammation, diabetes, and overseas air travel, but not mutations within the structural gene, F8. Recently, an association between depression and FVIII:C level has been reported. Goals: The first goal of this dissertation was to characterize the genetic variations in F8 using 222 X chromosomes. The second was to determine if any of the variants are associated with FVIII:C levels, controlling for appropriate variables. We then attempted to replicate the association in a different population of unrelated white and black women. Finally, we investigated the role of depression as a possible non-genetic determinant of FVIII activity levels in these women. Results: We identified 47 genetic variants in F8, including five missense mutations (W0255C, R0484H, R0776G, D1241E, and M2238V) and five SNPs in the promoter region. Two SNPs (G056010A and C092714G, which encodes D1241E) were strongly associated with FVIII:C levels and, in this study of 21 families, were also in allelic association (r2 = 0.84, unadjusted). We replicated the association of C092714 and FVIII:C level within the white subjects of the second study, but in the black subjects the result was not strong and included the possibility of no association. Due to resource limitations, we were unable to genotype G056010A. Among the black women depression was suggestively associated with higher FVIII:C levels, whereas among white women it was not. Finally, though not the focus of these investigations, we raised the possibility that VWF antigen level and Factor IX activity level may not be just confounders, but also intermediates in a complex, unknown system of coordinate regulation.
Table of Contents
Chapter 1. Introduction
I. Focus of the dissertation
II. Overview of the biological process of coagulation
A. Introduction
B. Zymogen precursors
C. Enzymatic coagulation cascade
D. The role of platelets
E. The importance of cofactors
F. Attenuation, inactivation, clearance, and fibrinolysis
III. Overview of the FVIII protein
A. Introduction
B. Structural organization
C. Biosynthesis
D. Post-translational modification
E. Secretion
F. Activation/Inactivation
G. Clearance
IV. Overview of measurement
A. Introduction
B. Antigen level
C. Activity level
D. Measurement variability
V. Overview of the genic data
A. Introduction
B. Overview of the F8 structural gene
C. Generating DNA sequence data
VI. Family-based studies
A. Introduction
B. Identity by descent / Degree of relation
C. Violations of Mendelian inheritance
D. Heritability
E. Linkage Analysis
VII. Determinants of FVIII:C Levels
A. Introduction
B. Environmental
C. Endogenous
VIII. FVIII:C levels and thrombosis
IX. Goals of the dissertation
Chapter 2. A sequence variation scan of the coagulation Factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels.
Abstract
Introduction
Patients, materials, and methodsResults
Discussion
Acknowledgements
Authorships
References
Chapter 3. The C allele of the Factor VIII (F8) 092714 single nucleotide polymorphism is additively associated with increased Factor VIII activity levels in white women, but only weakly associated in black women.
I. Introduction
II. Materials and Methods
A. Study Population
B. Genotyping
C. Statistical Analysis
III. Results
A. Main Findings
B. Sensitivity Analyses
C. Additional Adjustments
IV. Discussion
V. Appendix
A. Possible Selection bias
B. Control of confounding
C. Influential observations
D. Confounders or potentially co-regulated factors
Chapter 4. The association between Depression and plasma Factor VIII activity (FVIII:C) levels in reproductive aged women
I. Introduction
II. Materials and Methods
A. Study Population
B. CES-D instrument
C. Statistical Analysis.
III. Results
IV. Discussion
V. Appendix
A. Possible Selection bias
B. Impact of Adjustment for Factor IX and for VWF:Ag
Chapter 5. Conclusion
I. Goals, Brief Overview of Background, and Importance
A. FVIII is central to proper hemostasis
B. Epidemiologic and Public Health Importance
II. Review of Major Findings
A. Genetic Variation in F8
B. Association between F8 variants and FVIII:C level
C. Association between depression and FVIII:C level
D. New perspective on established covariates
III. Cohesion of results
A. Pre-requisite variant discovery
B. Replication is necessary
C. Adjustment for VWF:Ag and FIX:C level
D. Implication of replication
IV. Agreement with current knowledge
A. The association between C092714G and FVIII:C levels was novel
B. Depression and FVIII:C levels
V. Important Strengths
VI. Important Weaknesses
VII. Conclusions
A. FVIII has multiple forms
B. C092714G is associated with FVIII:C levels
C. The association between FVIII:C and depression was weakly supported
VIII. Future directions
A. Measurement of FVIII:Ag levels
B. Characterizing the proteins with which FVIII interacts
C. Explore associations with haplotypes
D. The role of Depression
E. Refine the definition of diabetes
References
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