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A Haplotype Analysis of the Angiotensin Converting Enzyme Gene in Ischaemic Stroke

By Gary Jon Dennis


Background: Epidemiological studies lend some support for a genetic predisposition to human stroke. There is a growing body of evidence to suggest a role for Angiotensin II (ANGII) in vascular disease. The levels of Angiotensin converting enzyme (ACE), which converts ANGI to ANGII, are known to be under a significant degree of genetic control. The D allele of the ACE I/D polymorphism is associated with higher serum ACE levels and this allele has also been associated with ischaemic stroke. Recent identification of numerous ACE single nucleotide polymorphisms has allowed for a more powerful case control haplotype analysis of ACE in ischaemic stroke. \ud Patients and Methods: The validity of the published structure of the common ACE haplotypes was investigated and supported using long range allele specific PCR and DNA sequencing of a random sample of UK caucasian subjects. Using restriction fragment length polymorphism (RFLP) analysis of selected polymorphisms we generated ACE haplotypes for 359 ischaemic stroke patients and 328 unrelated controls. \ud Results: Age, hypertension, smoking, diabetes and hypercholesterolaemia were identified as significant clinical risk factors for ischaemic stroke. D allele frequencies showed no significant differences between cases and controls (0.55 vs 0.53 respectively). However a low frequency D allele haplotype (H9) was found to be an independent risk factor for ischaemic stroke (odds ratio 2.05, p=0.004). \ud Conclusion: This study has provided allele specific data to support the haplotype structure of the common ACE haplotypes in a UK caucasian population. For the first time, in a case control analysis, we have identified a significant and independent genetic association of a low frequency ACE haplotype, H9, with human ischaemic stroke. This result suggests an important role for ACE in ischaemic stroke which will require further study in other populations using a variety of control groups

Publisher: University of Leicester
Year: 2008
OAI identifier: oai:lra.le.ac.uk:2381/8737

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