Muthumala, A.; (2008) The influence of ACE (I/D) polymorphism in cardiovascular disease. Doctoral thesis , University of London.

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Abstract

The renin-angiotensin system (RAS) is involved in maintenance of cardiovascular function and has been implicated in coronary heart disease (CHD) and type 2 diabetes (T2D). Pharmacological inhibition of the RAS improves cardiovascular disease outcomes. Angiotensin Converting Enzyme (principal component of RAS) levels are significantly associated with the ACE(I/D) polymorphism. Large studies have demonstrated a mild effect of this polymorphism on CHD risk. However the presence of RAS in diverse tissues implicated in cardiovascular diseases justify the hypothesis that genetic polymorphisms encoding proteins in this system 'modify' the risk of such diseases in the context of harmful stimuli or affect disease progression. This thesis therefore tested the hypothesis that the ACE(I/D) polymorphism 'modifies' risk of CHD and T2D, and affects progression of Hypertrophic Cardiomyopathy (HCM). Using a study of 532 myocardial infarction (MI) survivors and 574 controls (HIFMECH), an interaction between the ACE polymorphism and lipid levels on MI risk in Northern compared to Southern Europeans is demonstrated: the MI odds with high ApoB levels in D allele carriers was much greater in the North than the South. In a prospective cohort of 3052 healthy men (NPHS2), an interaction between ACE and systolic blood pressure (SBP) on CHD risk is presented where D allele carriers were protected against CHD at lower SBP, but at higher SBP were more susceptible. In the same study, ACE variants modified the risk of T2D in obese individuals, with obese D allele carriers having a substantially higher T2D risk compared to obese II homozygotes. From a retrospective study of 541 patients with HCM a possible effect of the polymorphism on left ventricular remodelling is demonstrated. Thus the work in this thesis offers strong evidence that the ACE gene modifies risk of CHD and T2D in the presence of known risk factors.

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