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Abstract: We have progressively analysed three studies of coronary heart disease (CHD) for a variant in EPCR (Ser219Gly). Initially, in a prospective study, NPHSII, while no overall CHD-risk was identified in heterozygotes, homozygotes for 219Gly exhibited a three-fold elevated risk (HR 3.3, CI 1.22–8.96). In diabetics within NPHSII, there was a suggestion that 219Gly+ was associated with elevated CHD-risk (HR 1.89, CI 0.39–9.06) although numbers were small. To further assess the effect of the variant in diabetes, a case–control study of MI, HIFMECH, was used, in which previous analysis had defined a group with metabolic syndrome, by factor analysis. A significant CHD-risk interaction was identified between genotype and the ‘metabolic syndrome’ factor (interaction p =0.009). To further assess CHD-risk for this variant in type-2 diabetes and to assess the effect of the variant upon thrombin generation and plasma levels of soluble EPCR, a cross-sectional study of type-2 diabetes was used. A significant CHD-risk was identified for European Whites (OR 2.84, CI 1.38–5.85) and Indian Asians in this study (OR 1.6, CI 1.00–2.57) and the frequency of 219Gly was two-fold higher in Indian Asians. Soluble EPCR levels were strongly associated with genotype, with homozygotes for 219Gly having four-fold higher levels (p <0.0001). In vitro studies of EPCR-transfected cells suggested increased basal release of sEPCR from cells expressing the 219Gly EPCR phenotype. Furthermore, in base-line samples from NPHSII and in the diabetic study, a significant increase in prothrombin F1+2 level was observed for 219Gly. The increased CHD-risk and thrombin generation appears to be acting through increased shedding of the Gly allele from the cell surface. [Copyright &y& Elsevier]

Abstract: In a previous case control study of myocardial infarction (MI), we identified risk associated with the combination of two variants in the thrombomodulin (TM) gene (-1208-1209TTdelTT and A455V) and an interaction with increased body mass index (BMI). The rare alleles at these two common variant sites in the TM gene occur in most individuals on the same allele (V/delTT) and are in strong linkage disequilibrium (Δ = 0.67, P < 0.0005). We have extended these findings in a prospective study of 2700 UK middle age men; the second Northwick Park Heart Study (NPHSII), in which 227 coronary heart disease (CHD) events have been reported to date. Risk was analysed by tertile of BMI, systolic blood pressure (SBP) and triglyceride. The strongest risk for the V/delTT haplotype was in the mid- and top-tertile of triglyceride; RR 1.95 (CI 1.12–3.40) and 1.77 (CI 1.02–3.09), respectively, compared to non-carriers in the lowest tertile (after adjusting for age, practice, smoking, SBP, BMI; interaction P = 0.016). No significant risk was identified for increased triglyceride levels in those with the common TM haplotype. There was a suggestion for greater inflammatory response (C-reactive protein levels, CRP) in those with V/delTT compared to those with the common allele, as triglyceride levels increased. Overall, these findings may suggest that the common TM allele confers protection against the adverse CHD effect of either plasma triglyceride-containing lipoproteins, or the underlying atherosclerotic mechanism of the metabolic syndrome, and that this process is defective in carriers of V/delTT. [Copyright &y& Elsevier]

Introduction: The tissue renin-angiotensin system is implicated in the pathogenesis of coronary artery disease (CAD). As locally synthesised aldosterone is a potential mediator of CAD, we have sought an association of the -344T>C variant of the aldosterone synthase (CYP11B2) gene with CAD events. Methods: Subjects comprised of the Second Northwick Park Heart Study (NPHSII), a prospective study of unrelated, healthy middle-aged Caucasian males. CAD events were recorded in 2490 subjects, and defined as a sudden cardiac death, myocardial infarction or coronary artery revascularisation procedure. Mean follow-up was 10.8 years. Aldosterone synthase genotype was determined in 2490 subjects. Power calculation suggests that we have 80% power (at a significance level of 0.05) to detect a difference in hazard ratio (HR) between homozygote groups of 0.45. Results: One hundred and eighty-seven CAD events were recorded in 2490 subjects. In the group overall, CAD events were independent of genotype with adjusted hazard ratios being 1.00 versus 1.25 versus 0.80 for TT versus TC versus CC genotypes, respectively, P=0.07. Genotype interactions with smoking and blood pressure were sought. Whilst CAD events were independent of genotype amongst non-smokers, CC genotype in smokers was associated with a reduced risk HR 2.02 versus 2.28 versus 0.82 for TT versus TC versus CC genotypes, P=0.05 (HR for TT + TC versus CC were 1.77 versus 0.67, P=0.02). This apparent interaction remained after adjustment for conventional risk factors. No such interaction was found with blood pressure. Conclusions: Aldosterone synthase genotype is unrelated to overall CAD events risk. A possible interaction with smoking requires confirmation. [Copyright &y& Elsevier]