More than 750,000 Americans suffer stroke each year. Of these, nearly 160,000 die and hundreds of thousands are disabled. The burden on the public health is even greater given that 11 million subclinical strokes per year contribute to cognitive decline and dementia. Ischemic stroke accounts for 85% of all strokes. Established stroke risk factors play major roles in defining stroke risk at a population level, but prediction of individual risk remains unrealized. Identification of factors that place individuals at risk for ischemic stroke is central to the development of therapeutic preventative strategies. The Vitamin Intervention for Stroke Prevention (VISP) trial, an NIH-funded, multicenter, double-blind, randomized, controlled clinical trial, was designed to determine whether the daily intake of high dose folic acid, vitamins B6 and B12 reduced recurrent cerebral infarction and a combined vascular endpoint. The question of benefit versus risk for B-vitamin supplementation remains a controversial topic. Concern that such interventions may incur measurable risk heightens the need to clarify who might benefit and who might be harmed by such therapies, particularly given population-level folate supplementation efforts. Our central hypothesis is that there are genetic variants that significantly correlate with risk of recurrent ischemic stroke in the setting of vitamin therapy.
The specific aims of this proposal are to: 1) Identify genetic variants that influence the risk of recurrent stroke or combined vascular endpoints in response to vitamin therapy;2) Determine whether the association between genetic variants and risk of recurrent stroke, MI or death is mediated via diet, inflammation, and/or coagulation;3) Develop predictive models, incorporating genetic and clinical information, that can be applied to future clinical trial design;4) Work collaboratively with other UOl awardees and the NHGRI to develop a paradigm for pharmacogenomic clinical trial design. The VISP trial provides a unique data set and a wealth of analytic opportunities. These analyses are expected generate testable models predictive of stroke risk, impart insights into pathophysiologies underlying susceptibility to ischemic stroke, and be instructive in providing a framework to develop guidelines for genome-wide studies on future clinical trials;
More than 750,000 Americans suffer stroke each year. Of these, nearly 160,000 die and hundreds of thousands are disabled. The burden on the public health is even greater given that 11 million subclinical strokes per year contribute to cognitive decline and dementia. Beyond the human cost, the direct and indirect costs of ischemic stroke in the U.S. are projected to exceed $2.2 trillion in 2050.
|Kong, Dehan; Maity, Arnab; Hsu, Fang-Chi et al. (2018) Rejoinder to ""A note on testing and estimation in marker-set association study using semiparametric quantile regression kernel machine"". Biometrics 74:767-768|
|Davis Armstrong, Nicole M; Chen, Wei-Min; Brewer, Michael S et al. (2018) Epigenome-Wide Analyses Identify Two Novel Associations With Recurrent Stroke in the Vitamin Intervention for Stroke Prevention Clinical Trial. Front Genet 9:358|
|Fernández-Cadenas, Israel; Mendióroz, Maite; Giralt, Dolors et al. (2017) GRECOS Project (Genotyping Recurrence Risk of Stroke): The Use of Genetics to Predict the Vascular Recurrence After Stroke. Stroke 48:1147-1153|
|Woo, Daniel; Debette, Stephanie; Anderson, Christopher (2017) 20th Workshop of the International Stroke Genetics Consortium, November 3-4, 2016, Milan, Italy: 2016.036 ISGC research priorities. Neurol Genet 3:S12-S18|
|Williams, Stephen R; Hsu, Fang-Chi; Keene, Keith L et al. (2017) Genetic Drivers of von Willebrand Factor Levels in an Ischemic Stroke Population and Association With Risk for Recurrent Stroke. Stroke 48:1444-1450|
|Kong, Dehan; Maity, Arnab; Hsu, Fang-Chi et al. (2016) Testing and estimation in marker-set association study using semiparametric quantile regression kernel machine. Biometrics 72:364-71|
|van der Laan, Sander W; Fall, Tove; Soumaré, Aicha et al. (2016) Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study. J Am Coll Cardiol 68:934-45|
|Holliday, Elizabeth G; Traylor, Matthew; Malik, Rainer et al. (2015) Genetic overlap between diagnostic subtypes of ischemic stroke. Stroke 46:615-9|
|Marceau, Rachel; Lu, Wenbin; Holloway, Shannon et al. (2015) A Fast Multiple-Kernel Method With Applications to Detect Gene-Environment Interaction. Genet Epidemiol 39:456-68|
|Carty, Cara L; Keene, Keith L; Cheng, Yu-Ching et al. (2015) Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans. Stroke 46:2063-8|
Showing the most recent 10 out of 18 publications