Leducq Center Against Small Vessel Disease

Significance of CADASIL/CARASIL-related genes/proteins and disease pathways for common SVD

Through studies described above, we (all members of the LCASVD) will examine the role of pathways predicted by proteomic and genomic analyses. Functional studies involving challenge with chronic infusion of Ang II via osmotic mini-pumps, initiated in Notch3 gain- and loss-of-function inducible mouse models (year 1), will be extended to mouse models of the most promising candidate genes. Because some vascular and brain lesions may not manifest during this relatively short-term Ang II infusion (~1 month), we plan to use interbreedings with genetic mouse models of life-long hypertension, such as transgenic mice that overexpress renin (Faraci, Joutel).

Genetic studies in humans will first investigate whether common variants in these genes modulate the risk of MRI markers of SVD in community participants aged >65 years from the 3C-Dijon study (Tzourio). We will focus primarily on white matter hyperintensity volume, an excellent quantitative marker for SVD-related cerebrovascular disease, with high heritability¹¹. In secondary analyses, we will study other MRI-markers of SVD, including lacunar brain infarcts and dilated perivascular spaces. Replication studies will be conducted in independent population-based samples, including the EVA Study and the CHARGE Consortium¹¹, as part of ongoing collaborations. We will also assess gene-environment interactions, especially with blood pressure, and gene-gene interactions.

A cohort of extensively phenotyped SVD patients will have been assembled by the end of year 2 (Chabriat). We will then be able to assess, as a second step, whether rare variants of genes identified in Aim 1 modulate the risk of symptomatic SVD. Rare genetic variants will be explored in at least 200 patients and controls with no brain infarcts or WMHV in the bottom tail of the distribution, selected from the 3C-Dijon Study. Next-generation sequencing employing the most appropriate platform will be used for this analysis (year 2-3). We will employ burden tests that assess the cumulative effects of multiple variants in the selected genomic regions (Tzourio). The significance of rare variants identified through these studies will be assessed in silico and in vitro as a first step, followed by functional studies in the mouse (Tzourio, Joutel).