This is a 2-year, revised-work scope competitive renewal for the Genetics of Microangiopathic Brain Injury (GMBI) study, initially funded in 2001 as an ancillalY study to the Genetic Epidemiology Network of Arteriopathy (GENOA) and Family Blood Pressure Program. In the initial GMBI grant cycle (2001-2006). we conducted genomewide linkage analyses and candidate gene association analyses to identify genes influencing leukoaraiosis, a heritable measure of ischemic brain injury determined by magnetic resonance imaging (MRI) of subcortical white matter hyperintensity volume in 883 non-Hispanic white and 795 nonHispanic black GMBI-GENOA participants ascertained through sibships with 2 or more members with essential hypertension. The 2?year revised?work scope research plan proposes a functional genomic strategy based on gene expression measurements to identify genetic variants influencing leukoaraiosis and other MRI measures of structural brain injury (cerebral atrophy and ventricular enlargement) associated with risk factors for arteriosclerosis and predictive of stroke and dementia. The power of the proposed approach derives from assessment of functional consequences of genomic variations associated with or linked to MRI measures of structural brain injury.
Aim 1 will determine whether DNA sequence variants previously found to influence MRI measures of structural brain injury may also have functional effects on heritable measures of gene expression in immortalized lymphocytes from 883 white GMBI participants.
Aim 2 will determine whether inter?individual variation in gene expression levels in immortalized lymphocytes, which provide quantitative indices of the heritable, functional effects of multiple DNA sequence variations in a gene region, are associated with MRI measures of structural brain injury in white GMBI participants.
Although genetic susceptibility is known to contribute to risk of stroke and dementia, most of the genes and the mechanisms by which injury to brain structure and function occurs remain unknown. Since genetically determined alterations in gene expression are likely to be a major mechanism accounting for statistical associations between genetic polymorph isms and variation in susceptibility to brain injury, this project will utilize a functional genomic strategy, based on gene expression profiles measured in human lymphocytes, to identify genetic variants that alter gene expression levels and thereby contribute to inter-individual differences in magnetic resonance imaging measures of structural brain injury. Such identification of genetic variants with functional effects contributing to alterations in structural brain injury may lead to improved methods of detection, evaluation, treatment, and prevention of stroke and dementia.
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