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Identification of the genetic risk-factors and the molecular mechanisms involved in the susceptibility to cerebrovascular disorders


The CerebroVascular Ischemic Disease (CVID) is a heterogeneous group of dysfunctions affecting the blood vessels supplying the brain. The most common outcome of CVID is ischemic stroke, an acute event that happens when the blood flow to a part of the brain is interrupted by a blood clot.

CVID is an important cause of disability and cognitive decline, resulting a major focus of health care and research.

Despite the existence of a minority of stroke cases ascribed to monogenic causes, the majority of CVID cases are characterized by a multifactorial aetiology in which both genetical and environmental factors play a role (1). Recently, it has been estimated that for ischemic stroke, heritability is 37.9% (2). However, until now, few predisposing loci have been identified and the genetic architecture of the disease is still sketched. 

Through a collaboration with the Cerebrovascular Diseases Unit at the Fondazione IRCCS Istituto Neurologico "Carlo Besta", we are carrying out a research project aimed at the identification and characterization of genetic factors and pathways involved in the aetiology of CVID. Using different statistical methods and bioinformatics tools we are analyzing the Italian cerebrovascular cohort established and genotyped at genome-wide level at the Besta Institute.

In particular, we participated to an international meta-analysis study with the aim of investigating the possibility that known myocardial infarction risk variants contribute to the aetiology of ischemic stroke. None of the variants that we analyzed was significantly associated with ischemic stroke, suggesting that the major myocardial infarction risk alleles do not increase the risk of having stroke (3). 

Moreover, we conducted a genome-wide association study with CVID in the Italian cohort to identify new risk factors. 709 cases and 956 controls, assessed for 487758 SNP, were tested in a case-control association study. We found two new good candidate risk regions, tagged by markers significantly associated with ischemic stroke. To test the validity of the initial associations, the SNPs significantly associated in the first step were analyzed in independent populations in collaboration with the International Stroke Genetics Consortium of which the Istituto Besta is a member. None of the SNPs analyzed was significantly associated in the replication cohort. We are now investigating the reasons of these negative results in order to conceive a new working hypothesis, identification suitable replication cohort.

Finally, to confirm and better characterize previously identified risk variants, we are also studying in our cohort some loci already reported as associated with stroke or other vascular disorders. In particular, we are studying the 9p21.3 genomic region, originally identified as a major risk locus for coronary artery disease and whose contribution to cerebrovascular disease aetiology is still poorly understood.


  1. Dichgans, M. Genetics of ischaemic stroke. The Lancet Neurology 6, 149–161 (2007).
  2. Bevan, S. et al. Genetic heritability of ischemic stroke and the contribution of previously reported candidate gene and genomewide associations. Stroke 43, 3161–3167 (2012).
  3. Cheng, YC. et al. Are myocardial infarction--associated single-nucleotide polymorphisms associated with ischemic stroke? Stroke 43, 980–986 (2012).


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