A combination of two common thrombomodulin gene variants (-1208-1209TTdelTT and A455V) influence risk of coronary heart disease: a prospective study in men

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.