BACKGROUND AND OBJECTIVE: Via direct sequencing, we have recently identified six common polymorphisms in angiotensin receptor-like 1 (AGTRL1) gene, and found only two polymorphisms were significantly associated with hypertension in a family-based analysis on 1,015 southern Han Chinese. Extending our previous work and considering the ubiquity of epistasis in determining disease susceptibility, we, in this study, sought to explore the potential interaction of AGTRL1 gene six polymorphisms with hypertension in a large northeastern Han Chinese population. METHODS AND RESULTS: This was a case-control study involving 1,009 sporadic hypertensive patients and 756 normotensive controls. Data were analyzed by Haplo.Stats and multifactor dimensionality reduction (MDR) softwares. There were no... deviations from Hardy-Weinberg equilibrium for all polymorphisms. The genotypes and alleles of rs7119675 and rs11544374 differed significantly between the two groups (P<0.0005), even after the Bonferroni correction. Under three genetic models, significant association was consistently observed for rs7119675 and rs11544374, and this association was independent of confounding factors. Taking rs7119375 as an example, the odds of having hypertension was 2.46 (95% confidence interval (95% CI): 2.06-2.94), 2.82 (95% CI: 2.29-3.46) and 3.97 (95% CI: 2.37-6.64) under additive, dominant and recessive models (P<0.001), respectively, whereas the adjusted risk estimates were slightly attenuated but still significant. The frequencies of most derived haplotypes differed significantly between patients and controls. Haplotype-phenotype analyses indicated marginal association for triglyceride (P(Sim) = 0.011) and total cholesterol (P(Sim) = 0.025) in patients and for triglyceride in controls (P(Sim) = 0.023). The overall best MDR model included rs11544374, rs7119375 and rs948847 with the maximal testing accuracy of 0.737 and cross-validation consistency of 10 out of 10 (P<0.0001). Further interaction entropy graph suggested that the interaction of rs7119375 with rs11544374 and rs948847 was strongly antagonized. CONCLUSIONS: Our findings demonstrate that AGTRL1 genetic polymorphisms might contribute to the development of hypertension independently and/or through complex interaction.