Molecular variants of individual components of the renin-angiotensin system are thought to contribute to inherited predisposition towards essential hypertension. Using polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and sequence analysis, we identified seven polymorphisms in the 5'-flanking region of the angiotensin II type 1 receptor (AGTR1/AT 1 ) gene. We conducted a case-control study in a sample from the Japanese population to determine whether polymorphic markers in the 5'-flanking region of the AT 1 gene were associated with essential hypertension. The study compared 149 hypertensive subjects to 156 normotensive control subjects. A significantly higher frequency of the AT 1 (-535)*T allele was observed in hypertensive subjects. Evidence was obtained that the AT 1 (-535)*T allele showed a synergistic effect on risk of hypertension with angiotensin I converting enzyme D allele (ACE*D).