Low Plasma Adiponectin in Risk of Type 2 Diabetes: Observational Analysis and One- and Two-Sample Mendelian Randomization Analyses in 756,219 Individuals.

We tested the hypothesis that low plasma adiponectin is observationally and genetic, causally associated with increased risk of type 2 diabetes. Observational analyses are prone to confounding and reverse causation, while genetic Mendelian randomization analyses are much less influenced by these biases. We examined 30,045 Copenhagen individuals observationally (1,751 type 2 diabetes; plasma adiponectin), 96,903 Copenhagen individuals using one-sample Mendelian randomization (5,012 type 2 diabetes; five genetic variants), and 659,316 Europeans (ADIPOGen, GERA, DIAGRAM, UK Biobank) using two-sample Mendelian randomization (62,892 type 2 diabetes; ten genetic variants). Observationally, and compared to individuals with median plasma adiponectin of 28.9μg/mL(4th quartile), multivariable adjusted hazard ratios for type 2 diabetes were 1.42(95% CI:1.18-1.72) for 19.2μg/mL(3rd quartile), 2.21(1.84-2.66) for 13.9μg/mL(2nd quartile), and 4.05(3.38-4.86) for 9.2μg/mL(1st quartile). Corresponding cumulative incidences for type 2 diabetes at age 70 were 3%, 7%, 11%, and 20%, respectively. A 1μg/mL lower plasma adiponectin conferred a hazard ratio for type 2 diabetes of 1.07(1.06-1.09), while genetic, causal risk ratios per 1 unit log-transformed lower plasma adiponectin were 1.13(0.83-1.53) in one-sample Mendelian randomization and 1.26(1.01-1.57) in two-sample Mendelian randomization. In conclusion, low plasma adiponectin is associated with increased risk of type 2 diabetes, an association that could represent a causal relationship.