Objective: To determine the role of candidate gene polymorphisms in patients who sustained myocardial infarction at a young age and examine their relationship, if any, to risk factors. Since angiotensin II is known to play a pathophysiological role at the myocardial and vascular level, the genes to be studied are those regulating the renin angiotensin system and tissue metabolism. Design: The risk factors and genetic profile is described in 117 young Indians with myocardial infarction recruited over a period of thirty months (Dec 1997 - Jun 1999). Controls comprised 80 normal subjects with no clinical evidence of coronary heart disease (CHD) and with a normal effort response. The key features of this study are the selection of young subjects with myocardial infarction, (mean age 43 ± 6.8 years) in whom the possibility of a genetic basis for the disease was felt to be more likely since the confounding effect of age as a risk factor was reduced. Setting: Patients recruited 3 -12 months after myocardial infarction from Addington Hospital, Durban. This hospital subserves the Indian community in the north of Durban. The majority of patients were from the Phoenix settlement area. Results: 1. The clinical profile of the young Indian with myocardial infarction is a young man, slightly overweight with a high prevalence of risk factors, particularly smoking and diabetes, coupled with sedentary behaviour and risk-prone dietary patterns characterised by high red meat intake and low fruit and vegetable consumption, resulting in increased BMI and W/H ratios. 2. There were no differences in the patterns of gene polymorphism in the reninangiotensin system between the study and control groups. This finding extended across all candidate gene loci studied i.e. those involving aldosterone, G-protein, TGF-B and homocysteine metabolism. Serum triglycerides, haemoglobin AlC and urine microalbumin levels were elevated in the probands together with low HDL-C levels (p = 0.001). 3. A striking finding of this study was the substantial proportion of patients found to have diabetes mellitus, totalling 47% of the proband group. Of the 53 diabetic patients, (45 males and 8 females) four (3 males, 1 female) had impaired glucose tolerance. Cigarette smoking, a positive family history of hypertension/diabetes and a family history for premature CHD emerged as important risk predictors for MI. Conclusion: This study, the first to report candidate gene polymorphisms in young Indians with coronary heart disease, has shown no obvious association between the genetic loci studied and acute myocardial infarction. Instead a high prevalence of risk factors, particularly smoking and diabetes mellitus, coupled with coronary-prone behavioural patterns was observed. In the light of these findings, genome-wide screening of unaffected siblings of subjects with early onset CHD cannot be recommended in this population until common polymorphisms can be clearly identified as risk factors. Indeed this study again supports the dire need for early, school level, education in behavioural lifestyle patterns and disease predisposition. The Indian community is a very high-risk group who should be targeted, not for secondary, but for primordial disease prevention measures. The study does not rule out the role of other candidate gene polymorphisms in the pathogenesis of CHD in these subjects. The high prevalence of diabetes and insulin resistance suggests that studies of genes regulating glucose and lipid metabolism should be pursued. Such candidate genes should include genes for lipoprotein lipase and paraoxonase polymorphisms which may explain the dyslipidaemia patterns in this group.

Thesis (Ph.D.)-University of Natal, Durban, 2000.