Title: Evaluation of the role of genetic variants associated with blood pressure in risk of lacunar stroke

Laboratory/Hospital: Grup d’Epidemiologia Genètica i Cardiovascular, IMIM; Servei de Neurologia, IMIM-Hospital del Mar.

Persons in charge of the project: Gavin Lucas (glucas@imim.es); Jordi Jimenez Conde (jjimenez@imas.imim.es).

Introduction:

Hypertension (HTN) is the most important modifiable risk factor for stroke, and may be particularly important for some subtypes of stroke such as that of lacunar etiology. Genetic factors contribute significantly to modifying risk of both HTN and stroke. We have recently contributed to large genetic studies that have identified more than 35 novel genetic loci associated with systolic and diastolic blood pressure, pulse pressure and mean arterial pressure, although the effects of individual loci on these traits are small. However, initial analyses indicate that the additive effects of these variants, represented by genetic scores, may be much larger, and may provide a better indication of genetic risk. We have also observed that genetic scores composed of these variants are associated with clinical endpoints for which hypertension is a risk factor, including coronary artery disease, measures of renal dysfunction, and stroke (The International Consortium for Blood Pressure GWAS, submitted). Since HTN does not carry the same risk for all stroke subtypes, it is now important to compare the role of these BP-associated genetic loci in risk of different stroke subtypes, particularly in lacunar stroke, for which HTN is thought to be the most important risk factor.

Objective:

Using a case-control study design, assess the effects on risk of lacunar, cardioembolic, and atherothrombotic stroke of 37 variants shown in large meta-analyses of genome-wide association studies to be robustly associated with BP phenotypes. The effects of these variants on disease will be analysed both individually and additively (as a genetic risk score), and will be compared between stroke subtypes.

Methods:

SNP genotyping and allele calling will be performed using the Applied Biosystems OpenArray genotyping platform at the Universitat Pompeu Fabra – CEXS, Barcelona, Spain. Data analysis will be performed at IMIM using established quality control and analysis pipelines.

Requirements:

Samples of extracted DNA for cases of lacunar, cardioembolic, or atherothrombotic stroke diagnosed according to the TOAST criteria, and age- and sex-matched controls if available. Samples should be of white Caucasian ethnicity.
DNA samples: 5μl of genomic DNA at a concentration of 50ng/μl (measured using Picogreen). If high concentrations of DNA are not available, genotyping may be performed after an initial PCR amplification step. In the latter case, samples should have a minimum concentration of 20ng/μl and a minimum volume of 5μl.

Project funding:

The cost of sending samples, as well as the genotyping and analyses will be covered by the Epidemiologia Genètica i Cardiovascular group, IMIM. Resulting publications will reflect the contribution of participating centres as co-authors.