In the search for stroke genes: a long and winding road

In spite of a significant improvement in control of numerous predisposing risk factors, stroke remains a major health problem and a common cause of death and disability in our societies. Genetic predisposition to stroke development exists and has been documented in both animal models and in humans. However, a precise definition of genetic factors responsible for common forms of stroke is still lacking, mainly due to its complex nature, the confounding presence of other predisposing risk factors, and the genetic heterogeneity of human populations. In contrast, important breakthroughs have been reached for monogenic forms of stroke, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). An animal model of stroke, the stroke-prone spontaneously hypertensive rat, has provided valuable information on genetic factors involved in stroke predisposition. Among them, the gene-encoding atrial natriuretic peptide has been identified as a stroke gene in both the stroke-prone spontaneously hypertensive rat and, subsequently, in two different human populations. In particular, structural alterations of the gene are consistently present in diseased individuals, suggesting an important role of mutation-dependent mechanisms in stroke predisposition. Finally, the recent use of intermediate disease phenotypes provides a reductionist approach that may contribute to important accumulating information on genes contributing to cerebrovascular accidents.