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Title: Strategies towards understanding the genetics of ischemic stroke
Author: Yadav, Sunaina
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Stroke is the second largest cause of death and disability in the world and 80% of all strokes are ischemic in nature. While most risk factors have been investigated in depth, others such as South Asian ethnicity, long term blood pressure variability and symptomatic carotid stenosis remain largely understudied. In order to understand the genetic etiology underlining ischemic stroke, it is important to study the genetic burden shouldered by these phenotypes as well. This thesis examined the genetics of ischemic stroke in the presence of the above risk factors using three independent lines of investigation: a) literature based meta-analysis, b) candidate gene based approach and c) genome-wide association study. Using a literature based meta-analysis comprising 2529 ischemic stroke cases and 2881 healthy controls, genetic risk variants associated with ischemic stroke in South Asians were investigated. Genes PDE4D SNP 83, ACE I/D and IL10 G1082A were associated with South Asian ischemic stroke risk, with no major differences in strength of association for the same susceptibility genes in other ethnic groups. A candidate gene study was conducted using 8295 ischemic stroke cases and 12722 controls of European ancestry to test the association of GWAS-derived blood pressure variability associated cluster of 17 NLGN1 intronic SNPs. The study did not confirm the risk association of NLGN1 with ischemic stroke. Finally, a genome-wide association study was conducted to identify novel gene variants associated with ≥ 50% carotid stenosis in ischemic stroke, using 1164 cases and 13,703 healthy controls from seven independent cohorts. Three genetic loci at LRIG1, ROBO1 and CAPN7 were found to be associated at genome-wide significance. The findings of this thesis provide new insights into the genetic mechanisms underpinning ischemic stroke, by examining genetic variants associated with unusual stroke related phenotypes. Future directions include replication of sentinel SNPs in larger study populations and a GWAS for South Asian ischemic stroke cases.
Supervisor: Sharma, Pankaj Sponsor: UK-India Education and Research Initiative
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available