Objective– To explore the association between epistasis among related genes of the renin-angiotensin system (RAS) and type 2 diabetes (T2D).

research design and methods– Gene polymorphisms were genotyped in 394 T2D patients and 418 healthy controls in this case-control study. We used the MDR method to identify gene-gene interactions.

Results– No single-locus was associated with T2D, except for the I/D polymorphism of ACE gene in female subjects. For multi-locus analyses, in male subjects the model of rs2106809 (ACE2), rs220721 (Mas), rs699 (AGT) and I/D (ACE) was significant (p=0.043). This combination was associated with a 4.00 times (95% CI 2.51-6.38, p<0.0001) greater prevalence of T2D. In female subjects the model of rs2106809 (ACE2), I/D (ACE) and rs1403543 (AGTR2) was significant (P=0.012). This three locus combination was associated with a 2.76 times (1.91-3.97, p<0.0001) greater prevalence of T2D.

Conclusions– Interactions among RAS related genes were associated with T2D in a Chinese population.