Online_appendix_20210804_REVISION_CLEAN.pdf (668.49 kB)

Low plasma adiponectin in risk of type 2 diabetes: observational analysis and one- and two-sample Mendelian randomization analyses in 756,219 individuals

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posted on 23.08.2021, 11:11 by Maria B. Nielsen, Yunus Çolak, Marianne Benn, Børge G. Nordestgaard

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.


The submitted project and MBN are supported by the Research Foundation for Health Research of the Capital Region of Denmark and Director Kurt Bønnelycke and Mrs. Grethe Bønnelyckes Foundation.