| Background: Angiotensinogen (AGT) is a vasopressor agent and is part of the Renin-Angiotensin System (RAS) which plays an essential role in blood pressure regulation. The M235T polymorphism in AGT has been inconsistently associated with both hypertension and cardiovascular disease. We examined the role of M235T in hypertension and myocardial infarction (MI) and investigated whether this polymorphism interacts with other risk factors. Methods: We genotyped a subset of 7,232 individuals from the INTERHEART population, a global case-control study and sought replication in a subset of 12,206 individuals from the DREAM/EpiDREAM trial. Results: The T variant was significantly associated with MI in the two largest INTERHEART populations, Europeans (P<0.036) and South Asians (P<0.0005). Interestingly, we observed a more significant result in females (P< 0.0002) compared to males (P< 0.01). M235T was also associated with hypertension in a weighted meta-analysis adjusted for age and sex in both INTERHEART (P<0.01) and DREAM/EpiDREAM (P<0.001). Testing for an association with MI after adjusting for hypertension did not greatly alter the odds ratios obtained prior to adjustment, suggesting that only part of the effect on MI can be attributed to hypertension. We further hypothesized that M235T may have a different effect in certain sub-groups. We tested for the association with MI within low risk and high risk subgroups separately and observed an interaction with MI risk factors across multiple ethnicities. The Breslow-Day test for homogeneity of effect size between the low and high risk groups in the combined analysis yielded P<0.002. This trend was also observed in the DREAM/EpiDREAM subset. Conclusion : These results confirm the association of the T variant of M235T with both MI and hypertension. In addition, they demonstrate that M235T interacts with known risk factors and is involved in the pathogenesis of MI independently of hypertension. |
