Plasma factor IX (f-IX) levels influence thrombosis risk. Recent discoveries from the Genetics Analysis of Idiopathic Thrombophilia (GAIT) Project demonstrate that: 1) the population variation in thrombosis risk has a high heritability (h2), equal to or > 60%, largely due to unknown genetic factors; 2) a substantial portion of these heritable factors influence thrombosis risk by modulating intermediate hemostasis traits like f-IX; 3) the variation in f-IX levels also involves a substantial genetic component (h2 about 40%) that is entirely unknown; and 4) the variation in thrombosis risk and f-IX levels are strongly correlated genetically (rho[sub g] about 60%), indicating a number of the f-IX quantitative trait loci (QTLs) also influence thrombosis risk. These findings strengthen our proposal because a number of these QTLs are likely to reside in the f-IX locus itself as the expression of this protein is largely regulated at transcriptional and post-transcriptional levels through molecular events involving elements in essential gene regions. Indeed, two f-IX cis-elements, one in the promoter (AE-5') and one in the 3'-UTR (AE-3'), are responsible for the increase in f-IX levels with age. This implies that some of the population variation in f-IX levels may be age-related. Since we found that both age-elements are polymorphic, G-793A in AE-5' and a dinucleotide repeat (DNR) in AE-3', these variations are candidate QTL for f-IX levels and thrombosis risk. Our hypothesis that these variations, along with a f-IX coding region polymorphism (A23387G), modulate f-IX levels and/or catalytic activity, and therefore influence thrombosis risk leads to these Aims:
Aim 1 : To determine if a single nucleotide (SNP), G-793A, located within an essential f-IX promoter element influences f-IX levels and thrombosis susceptibility.
Aim 2 : Determine if a polymorphic DNR, which is located in a regulatory element in the 3' -untranslated region (3' -UTR), influences f-IX mRNA stability, plasma f-IX levels and thrombosis risk.
Aim 3 : Determine if A23387G, a f-IX coding SNP non-conservatively substituting an alanine (Ala) residue for a conserved threonine (thr), influences the rate of f-IX activation, plasma f-IX levels and thrombosis risk. Our long-range goal is to provide more accurate diagnostic approaches, including pre-clinical pedisposition testing, by improving our understanding of the inherited liability to thrombosis, and ultimately to supply the foundation for identifying the interacting factors influencing hemostasis as potential therapeutic targets for more efficacious and safer anticoagulants and antithrombotic agents.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL072533-01
Application #
6582601
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Hasan, Ahmed AK
Project Start
2003-08-15
Project End
2007-07-31
Budget Start
2003-08-15
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$369,288
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Sauna, Zuben E; Lozier, Jay N; Kasper, Carol K et al. (2015) The intron-22-inverted F8 locus permits factor VIII synthesis: explanation for low inhibitor risk and a role for pharmacogenomics. Blood 125:223-8
Kim, Benjamin; Hing, Zachary A; Wu, Andrew et al. (2014) Single-nucleotide variations defining previously unreported ADAMTS13 haplotypes are associated with differential expression and activity of the VWF-cleaving protease in a Salvadoran congenital thrombotic thrombocytopenic purpura family. Br J Haematol 165:154-8
Pandey, Gouri Shankar; Yanover, Chen; Howard, Tom E et al. (2013) Polymorphisms in the F8 gene and MHC-II variants as risk factors for the development of inhibitory anti-factor VIII antibodies during the treatment of hemophilia a: a computational assessment. PLoS Comput Biol 9:e1003066
Pandey, Gouri Shankar; Yanover, Chen; Miller-Jenkins, Lisa M et al. (2013) Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A. Nat Med 19:1318-24
Pandey, Gouri Shankar; Tseng, Sandra C; Howard, Tom E et al. (2013) Detection of intracellular Factor VIII protein in peripheral blood mononuclear cells by flow cytometry. Biomed Res Int 2013:793502
Sauna, Z E; Ameri, A; Kim, B et al. (2012) Observations regarding the immunogenicity of BDD-rFVIII derived from a mechanistic personalized medicine perspective. J Thromb Haemost 10:1961-5
Howard, T E; Yanover, C; Mahlangu, J et al. (2011) Haemophilia management: time to get personal? Haemophilia 17:721-8
Viel, Kevin R; Ameri, Afshin; Abshire, Thomas C et al. (2009) Inhibitors of factor VIII in black patients with hemophilia. N Engl J Med 360:1618-27
Ameri, Afshin; Machiah, Deepa K; Tran, Thuy T et al. (2007) A nonstop mutation in the factor (F)X gene of a severely haemorrhagic patient with complete absence of coagulation FX. Thromb Haemost 98:1165-9
Xu, Feng; Previti, Mary Lou; Van Nostrand, William E (2007) Increased severity of hemorrhage in transgenic mice expressing cerebral protease nexin-2/amyloid beta-protein precursor. Stroke 38:2598-601