Stroke is the third leading cause of death and the leading cause of adult disability in the United States. More adults are affected by stroke each year than Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis or Parkinson's disease. Hemorrhagic strokes represent the most severe subtypes of stroke. An estimated 40-50% of hemorrhagic stroke victims will die. Half of this mortality occurs in the first two days aftr the stroke making prevention of paramount importance. Familial aggregation and heritability studies strongly support the existence of genetic risk factors for non-lobar and lobar ICH independent of hypertension and apolipoprotein E status. The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) and the Genetic Risks for Medication-Related Hemorrhagic Stroke (GOCHA) studies have led numerous advances in our understanding of the genetic epidemiology of hemorrhagic stroke and ICH in particular. Both studies were independently funded to perform genome wide association studies of ICH. Having completed enrollment, genotyping, analysis and finally meta-analysis, the studies have identified a genome-wide significant association with non-lobar ICH. The identification on Chr 1q22 overlies the identical region identified by the CHARGE consortium as association with the closely related phenotype of cerebral white matter disease. The finding overlies the polyamine modulating factor 1 (PMF1) gene, a novel location that was very unlikely to have been independently identified through candidate gene studies. Although PMF1 was initially identified as a cell growth regulator, it is the rate-limiting enzyme in the catabolic pathway of polyamine metabolism. Of particular interest to ICH and deep white matter hyperintensity and possibly to vascular cognitive impairment and small vessel ischemic disease, polyamines have been found to disrupt the blood brain barrier. We now propose to follow-up this seminal finding with deep sequencing of the candidate regions and gene expression studies over the regions in a collection of 500 non-lobar ICH cases and 300 frequency matched controls plus 700 publicly available controls. Unlike major genetic studies of the past decade, follow-up studies of specific regions (rather than genome-wide studies) require smaller sample sizes and a highly favorable cost. If successful, the current proposal will identify one of the first new risk factors for non-lobar and lobar ICH in a generation. These findings may have broad ranging impact on related phenotypes of vascular cognitive impairment, Alzheimer's disease and ischemic stroke.
This proposal follows up on a long standing investment into the genetic underpinnings of stroke and in particular intracerebral hemorrhage. A novel genetic region of interest has been identified and replicated and the current proposal is to further understand these regions through deep sequencing and gene expression studies. The hope is that a new target for treatment and prevention of stroke may be identified.
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