Since triglycerides (TG) are a major independent risk factor for coronary heart disease, understanding their genetic and environmental determinants is of major importance. Mouse models indicate an inverse relationship between levels of the newly identified apolipoprotein AV (APOAV) and TG concentrations. We have examined the relative influence of human APOA5 variants on plasma lipids, compared to the impact of variation in APOC3 and APOA4 which lie in the same cluster. Single nucleotide polymorphisms (SNPs) in APOA5 (S19W, -1131T>C) and APOA4 (T347S, Q360H) and an APOA4/A5 intergenic T>C SNP were examined in a large study of healthy middle-aged men (n=2808). APOA5 19WW and -1131CC men had 52% and 40% higher TG (P<0.003) compared to common allele homozygotes, respectively, effects which were independent and additive. APOA4 347SS men had 23% lower TG compared to TT men (P<0.002). Haplotype analysis was carried out to identify TG-raising alleles and included, in addition, four previously genotyped APOC3 SNPs (-2845T>G, -482C>T, 1100C>T, and 3238C>G). The major TG-raising alleles were defined by APOA5 W19 and APOC3 -482T. This suggests that the TG-lowering effect of APOA4 S347 might merely reflect the strong negative linkage disequilibrium with the common alleles of these variants. Thus variation in APOA5 is associated with differences in TGs in healthy men, independent of those previously reported for APOC3, while association between APOA4 and TG reflects linkage disequilibrium with these sites. The molecular mechanisms for these effects remain to be determined.

These data confirm the importance of the inflammatory system in the development of coronary heart disease. They suggest that, at least in part, the effect of the IL-6 -174G>C polymorphism on blood pressure is likely to be operating through inflammatory mechanisms, but the genotype effect on coronary heart disease risk is largely unexplained by its effect on blood pressure. The molecular mechanisms whereby genetically determined differences in plasma levels of IL-6 are having these effects remain to be determined.

Objective-The Apolipoprotein-related Mortality Risk (AMORIS) study concluded that the apolipoprotein (apo)B/apoA-I ratio was the best predictor of coronary heart disease (CHD) risk. We have compared the pairwise combinations of total cholesterol, triglycerides (TGs), apoB, high density lipoprotein (HDL) cholesterol, low density lipoprotein cholesterol, and apoA-I on CHD risk prediction in middle-aged men. Methods and Results-Healthy middle-aged men (nϭ2508), free of CHD at baseline, were examined prospectively. Over 6 years of follow-up, there were 163 CHD events (including acute myocardial infarction, coronary artery surgery, and ECG evidence of silent myocardial infarction). The relative risk (RR) of CHD associated with cholesterol, TGs, apoB, apoA-I, apoB/apoA-I, low density lipoprotein cholesterol, and HDL cholesterol were examined by survival analysis.The apoB/apoA-I ratio was associated with the strongest effect on the RR (3.58, 95% CI 2.08 to 6.19). In multivariate analysis, apoA-I had no significant effect on risk. Examining RR by quartiles, apoB and HDL in combination (RR 8.38, 95% CI 3.21 to 21.92) were better predictors of CHD risk than apoB and TGs (RR 4.05, 95% CI 1.57 to 6.23). However, apoB and TGs in combination added risk information over and above lifestyle factors, whereas apoB and HDL cholesterol did not. Conclusions-The combined evaluation of apoB with TGs provides useful diagnostic criteria for CHD risk. Key Words: follow-up studies Ⅲ apolipoprotein B Ⅲ triglycerides Ⅲ HDL cholesterol Ⅲ apolipoprotein A-I R aised cholesterol, 1 raised triglycerides (TGs), 2 low levels of HDL cholesterol (HDL-C), 3 and small dense LDLs 4 are all considered to be independent predictors of coronary heart disease (CHD) risk. However, there is mounting evidence indicating that measures of plasma apoB and apoA-I, over and above lipid measures, may be better predictors of CHD risk in adults 5,6 and in children. 7 Walldius et al 8 recently published results from the Apolipoprotein-related Mortality Risk (AMORIS) study of 175 553 men and women; these results clearly demonstrate the power of apoB, apoA-I, and the apoB/apoA-I ratio in predicting CHD risk, suggesting that the ratio of apoB/apoA-I helps define cholesterol transport and reverse cholesterol transport to and from the peripheral tissue. Furthermore, in that study, the value of apoB as a risk predictor was evident even at LDL cholesterol (LDL-C) levels below the median, showing the strength of apoB compared with LDL-C in evaluating CHD risk. Making use of the newly derived formulas for HDL-C and LDL-C estimates by Walldius et al, 8 we have examined the combination of TGs and cholesterol, TGs and apoB, HDL-C and apoB, apoB and apoA-I, and HDL-C with LDL-C in predicting CHD risk in a large prospective study of healthy middleaged men in the United Kingdom. Methods Study SampleHealthy men (nϭ3052), aged 50 to 61 years and registered with 9 general medical practices, were recruited for prospective surveillance. The study had full ethical approval, with subjects g...

Abstract-The thrombin-activatable fibrinolysis inhibitor (TAFI) is a recently described inhibitor of fibrinolysis that decreases plasminogen binding to the fibrin surface. The plasma TAFI concentration is almost entirely genetically determined. We investigated whether plasma TAFI levels and polymorphisms located in the TAFI gene could constitute risk markers of myocardial infarction (MI). Plasma TAFI antigen (Ag) levels were assayed by ELISA and 2 TAFI gene polymorphisms (Ala147Thr and Cϩ1542G in the 3Ј untranslated region) were determined in a large European case-control study. This study compared 598 men recruited 3 to 6 months after MI with 653 age-matched controls from North Europe (Stockholm, Sweden, and London, England) and South Europe (Marseilles, France, and San Giovanni Rotondo, Italy). A TAFI Ag value above the 90th percentile was associated with a significantly lower risk of MI (odds ratio 0.55, PϽ0.02), indicating that elevated TAFI may be protective against MI. As previously shown, the 2 TAFI gene polymorphisms were in strong linkage disequilibrium and were associated with the TAFI Ag concentration, with carriers of the Thr147 and 1542C alleles having higher levels (PϽ0.0005). These effects were similar in controls and cases and in each center. There was a difference in allele frequency between cases and controls for the Ala147Thr polymorphism, with Thr147 allele carriers being more frequent in controls than in cases in 2 centers, Stockholm (Pϭ0.03) and San Giovanni Rotondo (Pϭ0.03); the odds ratio for the entire cohort was 0.78 (PϽ0.05). In conclusion, patients with a recent MI presented lower values of TAFI Ag and higher frequencies of the "TAFI-decreasing" alleles. The geographical differences observed do not contribute to explaining the North-South gradient in MI risk in Europe. Key Words: thrombin-activatable fibrinolysis inhibitors Ⅲ myocardial infarction Ⅲ genetic polymorphisms Ⅲ fibrinolysis T he thrombin-activatable fibrinolysis inhibitor (TAFI), also known as procarboxypeptidase B and procarboxypeptidase U, has been recently described. 1-3 It can potently inhibit fibrinolysis by removing carboxy-terminal lysine residues from partially degraded fibrin, decreasing plasminogen binding on its surface. 4 -7 Because of its role in the fibrinolytic system, TAFI may be implicated in atherothrombotic diseases. Studies conducted in different animal models support a physiological role of TAFI in the regulation of fibrinolysis. 8 -11 In humans, van Tilburg et al, 12 have shown that an increased plasma TAFI antigen (Ag) concentration could be a risk marker for venous thrombosis. 12 In a pilot study of men with stable angina pectoris and angiographically verified coronary artery disease, it was found that the plasma levels of TAFI were significantly higher in the patients than in healthy population-based age-matched men. 13 The between-individual differences in plasma TAFI concentration are only partly explained by environmental factors, suggesting a strong influence of genetic factors. 14,15 The hum...