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Genetic interactions in modulating the phenotypes of a complex trait, such as insulin sensitivity, were usually taken for granted. However, this has not been commonly shown. Previous studies have suggested that both PPARγ2 and adiponectin genes could influence insulin sensitivity. Therefore it is likely that they could modulate insulin sensitivity through gene to gene interactions.We genotyped 1793 subjects of Chinese and Japanese descendents from 601 hypertensive families recruited in Sapphire study for a T94G in the adiponectin gene exon 2 and the PPARγ2 Pro12Ala polymorphisms. Serum insulin concentrations and insulin resistance index (HOMAIR) were used as the markers of insulin sensitivity.We found that the T allele of adiponectin gene was associated with a higher Ins60 and higher area under curve of insulin (AUCi) in OGTT utilizing all subjects in a mixed model that corrected for family effects. Important interactions between adiponectin and PPARγ2 genotypes were found in fasting insulin concentrations (Ins0), insulin concentrations at 2-h (Ins120) in OGTT and insulin resistance index (HOMAIR). The main effects of the PPARγ2 genotypes were in the plasma glucose concentrations in OGTT. In contrast, the main effects of adiponectin genotypes were in every insulin variable, including Ins0, Ins60, Ins120, AUCi and HOMAIR. The subjects carrying the adiponectinG allele and the PPARγ2Ala12 allele seemed to be more insulin sensitive.These results showed that adiponectin is a genetic factor associated with insulin sensitivity. Interactions with PPARγ2 genotypes modified this association.