A study of the genetic susceptibility to cerebral white matter lesions in patients with hypertension
01 / 2001 - 12 / 2004
Although the pathogenesis white matter lesions (WML) is unknown, these lesions are strongly correlated with cognitive (dys)function. Twin studies suggest a genetic susceptibility may underlie WML, in particular in patients with vascular disease. Hypertension is an important risk factor for WML. However, not all patients develop WML. Genes involved in the pathogenesis of hypertension may contribute to the heritability of WML. However, also genes not related to the etiology ot hypertension may be important in the development WML in patients with hypertension. Here we propose to embed within an ongoing program on the genetics of hypertension, a study which aims to localize genes determining the susceptibility to cerebral white matter lesions in patients with hypertension. The study is conducted in a genetically isolated population (GRIP1). In such a population the number of genes implicated in a complex trait such a WML is strongly reduced because of founder effects and genetic drift. Chances of success when screening the genome are therefore much better than in the general population. For the study of the genetics of WML, 400 patients with hypertension from GRIP1 will be examined by MRI. Given our earlier studies we expect to find at least 125 hypertensives with moderate or severe WML, of whom 75 will be included in a genome screen targeted to identify genes involved in the etiology of WML. All patients in whom WML has been assessed will be tested for the regions of interest identified in the search in order to disentangle whether the enlosed gene(s) are implicated in the etiology of WML, hypertension, or both. Although the isolation of the gene(s) is outside the scope of the project, risks associated with the gene(s) encaptured in the region(s) identified will be quantified in GRIP1 as well as in the scan study, a study of 1084 subjects randomly selected from the general Dutch population.