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A genome wide association study in patients with Intracranial Atherosclerosis

A genome wide association study in patients with Intracranial Atherosclerosis

Principal Investigator: Mr Israel Fernandez-Cadenas
Approved Research ID: 51946
Approval date: March 4th 2020

Lay summary

Large-artery intracranial atherosclerosis (ICAs) is a major cause of stroke worldwide. Different clinical risk factors have been associated with risk of ICAs. However, there is still a gap in the knowledge of the physiopathology of the disease. Furtheremore, there is not any drug to prevent or treat stroke in patients with ICAs. 


Genome-Wide Association studies (GWAs) have identified 6 loci associated with large-artery stroke. However, no GWAs has been performed to find genetic variants associated with ICAs. Given the relevance that genetics seems to have in this pathology, our aim is to identify genetic risk factors associated with ICAs using a GWAs approach. This data could help to identify key factors for this disease. These factors could be then targetted by existing or new drugs. Some studies from Astrazeneca has demonstrated that drugs developed using GWAs data have a very higher probability to be used in clinics than drugs developed from animal studies.


We have analyzed 107 patients with ICAs (94.6%symptomatic) and 316 population-based controls and we have replicated the results in two cohorts of 444 and 1,270 stroke patients attributed to intracranial and extracranial atherosclerosis, respectively, and 25,643 controls.  We have identified one locus at 18q22 associated with the presence of ICAs. This region was replicated in an independent cohort f (p-value=0.009 for the top SNP1).  There was no evidence for association of this polymorphism with extracranial atherosclerosis.

This locus is located near a prostaglandin-reductase gene previously associated with VEGF levels. This protein has been previously related with developement and progression of angiogenesis. Angiogenesis is a kew factor in the progression of patients after suffering a stroke.  Further studies are needed to really see the implication of the polymorphisms in angiogenesis.


Now, our aim is to do a GWAs meta-analysis with the UK Biobank data, including all patients with stroke attributed to intracranial stenosis or occlusion in order to increase the sample size and to identify new polymorphisms associated with this disease. Furthermore, the polymophisms identified will be further studied to find biological implications.