Interestingly, ADIPOQ SNPs that showed genome-wide significant associations with adiponectin levels did not show associations with T2D or CHD. This raises the question of how ARL15 interacts with adiponectin to influence disease risk. The demonstrated relationship of ARL15 with the metabolic traits and diseases may represent adiponectin-independent effects of ARL15 — a hypothesis that could be tested by adjusting the relationship between ARL15 and CHD or T2D for adiponectin levels (which was not possible in this study, as the disease cohorts had no measured adiponectin levels). Alternatively, recent evidence suggests that adiponectin may be influenced directly by insulin exposure [26]–[35], allowing adiponectin to act as a surrogate marker for integrated total insulin exposure as a result of its stable half-life and relatively low diurnal variability. Consequently, ARL15 may be an upstream mediator of the relationship between insulin and adiponectin, and may thus impact upon T2D and CHD through an insulin-dependent pathway which involves, but is not entirely dependent upon, adiponectin. In addition, since we demonstrated that the ARL15 variant was associated with adiponectin levels across all age ranges, including children
