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Genetic determinants of baseline levels and the fall in plasma triglyceride and fibrinogen levels in response to bezafibrate treatment were examined in 853 men taking part in the lower extremity arterial disease event reduction (LEADER) trial. Three polymorphisms in the peroxisome proliferator activated receptor alpha (PPARalpha) gene were investigated (L162V, G>A in intron 2 and G>C in intron 7), two in the apolipoprotein CIII (APOC3) gene (-482C>T and -455T>C) and one in the beta-fibrinogen (FIBB) gene (-455G>A). The presence of diabetes (n=158) was associated with 15% higher triglyceride levels at baseline compared to non-diabetics (n=654) (P<0.05). Among the diabetic group, carriers of the PPARalpha intron 7 C allele had 20% lower triglyceride levels compared to homozygotes for the common G allele (P<0.05), with a similar (non-significant) trend for the L162V polymorphism, which is in linkage disequilibrium with the intron 7 polymorphism. For the APOC3 gene, carriers of the -482T allele had 13% lower baseline triglyceride levels compared to -482C homozygotes (P<0.02), but no effect was observed with the -455T>C substitution. In the non-diabetic patients, the PPARalpha V162 allele was significantly associated with 9% higher baseline triglyceride levels (P<0.03) and a similar, but non-significant trend was seen for the intron 7 polymorphism. Overall, triglyceride levels fell by 26% with 3 months of bezafibrate treatment, and current smokers showed a poorer response compared to ex/non-smokers (23% fall compared to 28% P=0.03), but none of the genotypes examined had a significant influence on the magnitude of response. Carriers of the -455A polymorphism of the FIBB gene had, as expected, marginally higher baseline fibrinogen levels, 3.43 versus 3.36 g/l (P=0.055), but this polymorphism did not affect response to treatment. Overall, fibrinogen levels fell by 12%, with patients with the highest baseline fibrinogen levels showing the greatest decrease in response to bezafibrate. For both the intron 2 and the L162V polymorphisms of the PPARalpha gene there was a significant interaction (both P<0.01) between genotype and baseline levels of fibrinogen on the response of fibrinogen levels to bezafibrate, such that individuals carrying the rare alleles in the lowest tertile showed essentially no overall decrease compared to a 0.18 g/l fall in homozygotes for the common allele. Thus while these genotypes are a minor determinant of baseline triglyceride and fibrinogen levels, there is little evidence from this study that the magnitude of response to bezafibrate treatment in men with peripheral vascular disease is determined by variation at these loci.

Nine adults took two 7-day diets of standardised energy and total fat content, but with a dietary polyunsaturated/saturated fat ratio of less than 0.3 and greater than 3.0 respectively, while adhering to their daily routine. Blood was drawn on 6 occasions between 09.00 and 22.45 h on the final day of each dietary period for factor VII activity (VIIc), factor VII antigen (VIIag) and lipoprotein lipid concentrations. Diurnal variation was described for each variable in terms of its deviation from the individual's daily mean value at each time point across the day. Plasma triglyceride remained low until after the midday meal, whereafter a marked rise was sustained into the later evening. Plasma VIIc declined until early afternoon, but showed a marked rise in the late afternoon. Plasma VIIag showed no significant diurnal variation. Changes in plasma triglyceride concentration during the day were related positively to changes in VIIc about 160 min later, but not to VIIc at other time points. This effect of postprandial triglyceridaemia on VIIc persisted after allowance for the effect of VIIag on VIIc. Dietary fat composition did not influence VIIc or VIIag. The results suggested an acute but evanescent effect of triglyceride-rich lipoproteins on the reactivity of factor VII, irrespective of their lipid core composition.

Elevated plasma levels of low density cholesterol and their major apolipoprotein (apo B) are associated with an increased risk of coronary artery disease (CAD). We have examined allele frequencies of restriction fragment length polymorphisms (RFLP) of the apo B gene in 111 male Caucasians with premature CAD (mean age 49 +/- 7 years) and in 122 elderly Caucasian males (mean age, 73 +/- 5 years), free of clinical cardiovascular disease. The rare allele (R1) of the EcoR1 RFLP in exon 29, resulting in an amino acid change (Glu----Lys4154) was seen more frequently in CAD than in controls (0.270 vs 0.207, P less than 0.05). The R1 RFLP and the MspI insertion polymorphisms (MI) within the 3' hypervariable region (HVR) were observed together in 87% and are likely in linkage disequilibrium. The MI RFLP were slightly more frequent in CAD than control (0.239 vs. 0.211, P = 0.08). A second MspI RFLP in exon 26 results in an amino acid change (Arg----Glu3611); the rare allele M2 was seen more frequently in patients than in controls (0.150 vs. 0.057, P less than 0.005). No significant differences in allele frequencies were observed for the Xba1 RFLP in exon 26 (0.500 vs. 0.529, P = ns) or for the PvuII RFLP near the 5' end (P2) (0.105 vs. 0.088, P = ns). No statistically significant differences in lipid, lipoprotein cholesterol or apolipoproteins A-I and B were observed in patients or in controls. Two of the RFLPs examined (R1 and M2) result in changes in amino acid sequence and their allele frequencies are increased in CAD cases when compared with controls. Genetic variability within the apo B gene may thus contribute to cardiovascular risk. The physiological effects of individual mutations within apo B remain to be determined. It is unlikely, however that the single site polymorphisms examined in this study, will impart further information about CAD risk than conventional lipid parameters.

Repeated measurements were made in 8 adults of factor VII coagulant activity (VIIc) and fibrinogen concentration (two haemostatic variables associated with cardiovascular mortality), together with factor VII concentration, factor X, prothrombin, and serum cholesterol and triglyceride concentrations, while the usual diet was recorded by precise weighing over 12-14 days. In 6 subjects measurements were continued while low-fat and high-fat diets were taken for a further 2 and 3 weeks respectively. Plasma VIIc was related positively and independently to fat and protein intake, whereas factor VII concentration was associated only with protein consumption. In a second study, consumption of 50% extra energy for one day increased VIIc significantly when taken mainly as fat but not when taken mostly as carbohydrate. The character of the VIIc response to fat intake suggested an association with post-prandial lipaemia. A high fat intake may lead not only to coronary atheroma but also to fibrin deposition and thrombus formation through direct activation of the coagulation system.

Factor VII coagulant activity (VIIc) is considerably higher in rabbits fed a 1% cholesterol-supplemented diet than in rabbits fed a standard diet. This increase was statistically significant 4-6 days from the beginning of treatment and rose to about 300% during the 100 days of treatment. Treatment is also associated with a 20-fold increase in plasma cholesterol concentration with the major fraction of excess cholesterol associated with the very low and intermediate density lipoprotein fractions. In both groups of rabbits, the direction and extent of variation in VIIc generally coincided with variation in cholesterol, so that over time there were significant and positive correlations between plasma cholesterol concentration in both the rabbits fed the standard diet and the rabbits fed the cholesterol-supplemented diet. The increase in VIIc was due to a higher proportion of the more active alpha VIIa in the plasma of hypercholesterolaemic rabbits rather than to an increase in the concentration of the single-chain protein. The plasma concentration of factor X and prothrombin had increased in the hypercholesterolaemic rabbits by 10 days from the beginning of treatment and both proteins were maintained at 150-200% of the concentrations in the plasma of rabbits fed the standard diet. However, these differences were only seen when the factor X and prothrombin were assayed using synthetic substrates. The specific coagulation assays for these two factors revealed no differences between the groups of animals up to 100 days.

The origins of the high standardized mortality ratio (SMR) for coronary heart disease (CHD) among Indians in Britain, and the low SMR for West Indian immigrants, have been explored by a community survey in London. Serum lipoproteins, plasma glucose, haemostatic factors and other putative risk characteristics were measured in 75 Indian, 64 European and 24 West Indian men aged 45-54 years. These represented 81% of men registered with a general practice and resident within a defined area. In 51 men, diet was assessed by 5-day weighed inventory. Plasma phospholipid fatty acids (PFA) were measured in 18 Indians and 19 Europeans with dietary records. The relatively high HDL and HDL2-cholesterol concentrations, low LDL-cholesterol concentration, reduced fat intake, increased ratio of dietary polyunsaturated/saturated fat, relatively frequent use of alcohol, and lack of obesity in West Indians accorded with their low SMR from CHD. By contrast, only the relatively low HDL and HDL2-cholesterol concentrations, infrequency of alcohol consumption, and lower proportion of PFA as n-3 fatty acids of marine origin afforded explanations for the high SMR of Indians. Hyperglycaemia appeared similarly prevalent in Indians and West Indians, but less common in Europeans. Of the haemostatic factors, West Indians had a relatively low VIIc (not statistically significant), while Indians had an increased platelet count and reduced platelet volume. Improved understanding of these ethnic differences in CHD mortality may depend upon elucidation of the contrasts in HDL-cholesterol concentration.