Background: Components of the renin-angiotensin (R-A) system have been repeatedly investigated as candidate genes for essential hypertension. In particular, suggestive or significant association has been detected in some studies for the angiotensinogen M235T, angiotensin I-converting enzyme I/D, angiotensin II type 1 receptor A1166C, and aldosterone synthase C-344T polymorphisms, although the results remain inconclusive.
Objective and methods: To evaluate the importance of these candidate genes for hypertension, we undertook an extensive association study in the Japanese. This case-control study was conducted in a total of 1476 individuals using the four R-A gene polymorphisms. In the assessment of genotyping data, 843 hypertensive subjects were divided into three case subgroups according to severity of hypertension, while 633 normotensive subjects divided into two control subgroups by the age of enrollment. Each subgroup was further divided by sex. Subsequently, the presence of synergy (or gene-gene interaction) was evaluated among four R-A gene polymorphisms.
Results: No significant association was observed between the individual R-A gene polymorphisms and hypertension status in our case-control study. The results were almost unchanged when severity of hypertension, sex-specificity, and synergy were taken into account
Conclusions: Despite a relatively large number of subjects, we did not find significant evidence for disease association in the Japanese population. Given confounding factors in the case-control strategy, the lack of association does not exclude the relevance of the R-A genes to hypertension. Further investigation needs to be performed in large-scale populations, where the use of not only hypertension status, but also 'intermediate' phenotypes would be useful.