ObjectiveTo examine the interaction of sodium intake with genetic variations of the angiotensinogen gene and hypertension.DesignA community-based case-reference study.SettingTwo rural Japanese communities.ParticipantsNon-overweight and non-drinking Japanese men and women: 229 hypertensives and 229 age-, sex- and community-matched normotensives aged 32 to 83 years.MethodsPolymorphisms of the angiotensinogen gene detected by an allele-specific polymerase chain reaction. A priori hypothesis is individuals with 174M (threonine-to-methionine substitution) or 235T (methionine-to-threonine substitution) allelic variations may have an elevated risk of hypertension when they have a high sodium intake, estimated by 24-h urine collection and a dietary questionnaire.ResultsThe genotypic frequency of the haplotype including both the 174M and 235T alleles was higher among hypertensives than among normotensives (23 versus 14%,P= 0.02). The frequency of the 174M allele was specifically higher among hypertensives than normotensives (12 versus 7%,P= 0.01), and the odds ratio of hypertension associated with the 174M (versus 174T) allele was 1.8 [95% confidence interval (CI) 1.1–3.0,P= 0.01]. The frequency of the 235T allele did not vary between the two groups (80 versus 82%,P= 0.40). The relationship between the 174M allele and hypertension was more evident among persons who had higher urinary sodium excretion (> = 166 mmol/day) than those with lower excretion (< 166 mmol/day): odds ratio 2.5 (95% CI, 1.2–5.2),P= 0.01 versus 1.5 (95% CI, 0.7–3.1),P= 0.31;Pfor interaction = 0.04, and this trend was primarily observed for early-onset hypertension (< 55 years at onset). A similar but nonsignificant association was observed when stratified using present and past sodium intake scores derived from questionnaires.ConclusionAngiotensinogen genotype may affect the development of early-onset hypertension among Japanese, particularly in those who have a high sodium intake.