Influence of Genetic Risk Factors on Coronary Heart Disease Occurrence in Afro-Caribbeans.

BACKGROUND: Despite excessive rates of cardiovascular risk factors such as hypertension, diabetes, and obesity, Afro-Caribbeans have lower mortality rates from coronary heart disease (CHD) than do whites. This study evaluated the association of genetic risk markers previously identified in whites and CHD in Afro-Caribbeans. METHODS: We studied 537 Afro-Caribbean individuals (178 CHD cases and 359 controls) who were genotyped for 19 CHD-related single-nucleotide polymorphisms (SNPs). A genetic risk score (GRS) incorporating the 19 SNPs was calculated. These participants were compared with 1360 white individuals from the Second Northwick Park Heart Study. RESULTS: In Afro-Caribbeans, patients with CHD had higher rates of hypertension (78.7% vs 30.1%), hypercholesterolemia (52.8% vs 15.0%), and diabetes (53.9% vs 14.8%) and were more often men (64.0% vs 43.7%) and smokers (27.5% vs 13.4%) compared with non-CHD controls (all P < 0.001). The GRS was higher in Afro-Caribbeans with CHD than in those without CHD (13.90 vs 13.17; P < 0.001) and was significantly associated with CHD after adjustment for cardiovascular risk factors, with an odds ratio of 1.40 (95% confidence interval, 1.09-1.80) per standard deviation change. There were significant differences in allelic distributions between the 2 ethnic groups for 14 of the 19 SNPs. The GRS was substantially lower in Afro-Caribbean controls compared with white controls (13.17 vs 16.59; P < 0.001). CONCLUSIONS: This study demonstrates that a multilocus GRS composed of 19 SNPs associated with CHD in whites is a strong predictor of the disease in Afro-Caribbeans. The differences in CHD occurrence between Afro-Caribbeans and whites might be a result of significant discrepancies in common gene variant distribution.

The PCSK9 gene R46L variant is associated with lower plasma lipid levels and cardiovascular risk in healthy U.K. men.

In the present study, we have determined the relative frequency of the R46L, I474V and E670G variants in the PCSK9 (protein convertase subtilisin/kexin type 9) gene and its association with plasma lipid levels and CHD (coronary heart disease) in healthy U.K. men and patients with clinically defined definite FH (familial hypercholesterolaemia). Genotypes were determined using PCR and restriction enzyme digestion in 2444 healthy middle-aged (50-61 years) men from the prospective NPHSII (Second Northwick Park Heart Study), with 275 CHD events (15 years of follow-up), and in 597 U.K. FH patients from the Simon Broome Register. In the NPHSII healthy men, the R46L genotype distribution was in Hardy-Weinberg equilibrium and the frequency of 46L was 0.010 [95% CI (confidence interval), 0.007-0.013], with one man homozygous for the 46L allele. There was significant association of the 46L allele with lower mean (S.D.) total cholesterol [5.74 (1.01) mmol/l for RR compared with 5.26+/-1.03 mmol/l for RL; P=0.001], apolipoprotein B [0.87 (0.24) g/l for RR compared with 0.75 (0.26) g/l for RL; P<0.0001] and low-density lipoprotein cholesterol [4.01 (0.95) mmol/l for RR compared with 3.62 (0.97) mmol/l for RL; P=0.02]) levels, after adjustment for age, general medical practice, smoking, body mass index and systolic blood pressure. As expected, 46L carriers had a low risk of definite or possible CHD [hazard ratio, 0.46 (95% CI, 0.11-1.84)], but this was not statistically significant (P=0.27). Two other common PCSK9 variants I474V [V allele frequency, 0.179 (95% CI, 0.17-0.19)] and E670G [G allele frequency, 0.034 (CI, 0.03-0.04)] were not associated with any significant effects on lipid levels or CHD risk. In FH patients, the frequency of 46L was 0.003 (95% CI, 0.00-0.01), which was significantly lower (P=0.037) than the healthy subjects. In the four FH patients carrying 46L, mean untreated total cholesterol levels were not different (P=0.91) in carriers and non-carriers (median, 10.3 mmol/l compared with 10.2 mmol/l respectively, after adjustment for age, gender and mutation type). In conclusion, the PCSK9 46L allele is more frequent in healthy U.K. men than in FH patients and is strongly associated with a protective plasma lipid profile risk for CHD. Its low frequency (approx. 2% carriers) means that it does not make a major contribution to determining population CHD risk in the U.K.

The A370T variant (StuI polymorphism) in the LDL receptor gene is not associated with plasma lipid levels or cardiovascular risk in UK men.

Over 800 different missense mutations in the low density lipoprotein (LDL) receptor gene (LDLR) have been identified in patients with familial hypercholesterolaemia (FH). Only two of them, including the Alanine to Threonine change at position 370 (A370T), have been discovered in FH patients but do not cause FH. The frequency of the 370T allele has been reported worldwide to be between 0.022 and 0.070, with no clear association with high cholesterol levels or risk for coronary heart disease (CHD) and stroke. To explore this relationship in more detail we have determined this genotype in 2,659 healthy middle-aged (50-61 years) men participating in the prospective Second Northwick Park Heart Study, with 236 CHD and 67 stroke incident events. The genotype distribution was in Hardy-Weinberg equilibrium and in the no-event group the frequency of 370T was 0.046 (95% CI 0.040-0.052). Overall, there was no significant association of the 370T allele with any measured plasma lipid trait, and there was no difference in genotype distribution or allele frequency between the no-event and CHD (0.059; 95% CI 0.040-0.085) or stroke (0.037; 95% CI 0.012-0.085) groups ( p= 0.18 and 0.65, respectively). There was evidence for significant interaction ( p= 0.006) between body mass index (BMI) and genotype on CHD risk, with 370A homozygotes showing the expected higher CHD risk for those with higher BMI, whilst risk for 370T allele carriers was highest in men in the lowest tertile of BMI. The explanation for this association is unclear, and may simply be chance. Thus, these data confirm the absence of a significant impact of the A370T polymorphism on LDL receptor function, at least as measured by the effect on plasma lipid levels and CHD risk.

Cardiorespiratory fitness, all-cause mortality, and risk of cardiovascular disease in Trinidadian men--the St James survey

BACKGROUND: This study examined whether cardiorespiratory fitness is a risk factor for cardiovascular disease, myocardial infarction, and all-cause mortality in a low- to middle-income Trinidadian community of African, South Asian Indian, and European origin. Those of Indian descent have a distinctively high rate of myocardial infarction. METHODS: The St James Study is a prospective total community survey located in Port-of-Spain, Trinidad, West Indies. A random sample of 626 men aged 35-69 years, without angina of effort, previous myocardial infarction, partial or complete atrio-ventricular conduction defect, complete heart block, or exercise-induced asthma, was used for the assessment of cardiorespiratory fitness by cycle ergometry. Surveillance for morbidity and mortality was maintained for an average of 7.3 years. RESULTS: When the subjects were grouped into those with an age- and fat-free mass-adjusted peak oxygen uptake above and below the mean of 60.4 mmol/min (1.34 l/min), the hazard ratios (below/above) (95% confidence interval) for all-cause mortality, cardiovascular disease incidence, and incidence of myocardial infarction, after allowance for conventional cardiovascular risk factors, were 2.08 (1.23-3.52), 2.13 (1.22-3.69), and 2.36 (0.84-6.67), respectively. For those unable to achieve a level of work requiring an oxygen uptake of 67 mmol/min (1.5 l/min) during progressive exercise, the respective hazard ratios were 3.49 (1.57-7.76), 2.29 (1.21-4.33), and 5.45 (1.22-24.34). Indian ethnicity remained a predictor of myocardial infarction after allowance for cardiorespiratory performance. CONCLUSION: Low cardiorespiratory fitness is a risk factor for cardiovascular disease morbidity and mortality in the low- to middle-income developing community of Trinidad.

Cardiorespiratory fitness, all-cause mortality, and risk of cardiovascular disease in Trinidadian men--the St James survey.

BACKGROUND: This study examined whether cardiorespiratory fitness is a risk factor for cardiovascular disease, myocardial infarction, and all-cause mortality in a low- to middle-income Trinidadian community of African, South Asian Indian, and European origin. Those of Indian descent have a distinctively high rate of myocardial infarction. METHODS: The St James Study is a prospective total community survey located in Port-of-Spain, Trinidad, West Indies. A random sample of 626 men aged 35-69 years, without angina of effort, previous myocardial infarction, partial or complete atrio-ventricular conduction defect, complete heart block, or exercise-induced asthma, was used for the assessment of cardiorespiratory fitness by cycle ergometry. Surveillance for morbidity and mortality was maintained for an average of 7.3 years. RESULTS: When the subjects were grouped into those with an age- and fat-free mass-adjusted peak oxygen uptake above and below the mean of 60.4 mmol/min (1.34 l/min), the hazard ratios (below/above) (95% confidence interval) for all-cause mortality, cardiovascular disease incidence, and incidence of myocardial infarction, after allowance for conventional cardiovascular risk factors, were 2.08 (1.23-3.52), 2.13 (1.22-3.69), and 2.36 (0.84-6.67), respectively. For those unable to achieve a level of work requiring an oxygen uptake of 67 mmol/min (1.5 l/min) during progressive exercise, the respective hazard ratios were 3.49 (1.57-7.76), 2.29 (1.21-4.33), and 5.45 (1.22-24.34). Indian ethnicity remained a predictor of myocardial infarction after allowance for cardiorespiratory performance. CONCLUSION: Low cardiorespiratory fitness is a risk factor for cardiovascular disease morbidity and mortality in the low- to middle-income developing community of Trinidad.