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Comment
. 2013 Apr;62(4):1007-9.
doi: 10.2337/db12-1673.

A tangled threesome: adiponectin, insulin sensitivity, and adiposity: can Mendelian randomization sort out causality?

Jorge R Kizer  1
Affiliations
Comment

A tangled threesome: adiponectin, insulin sensitivity, and adiposity: can Mendelian randomization sort out causality?

Jorge R Kizer. Diabetes. 2013 Apr.
No abstract available

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Figures

FIG. 1.
FIG. 1.
Relations among AdipoQ variants, circulating adiponectin, adiposity, and insulin sensitivity/insulinemia with known or potential bearing on the interpretation of a corresponding MR analysis. Red arrows represent proposed causal associations, whereas blue arrows represent accepted causal associations. “A” denotes mediation of a causal adiponectin–insulin sensitivity association by adiposity, the most tenable interpretation of the MR findings reported by Gao et al. under a scenario in which all three of the fundamental assumptions of IV analysis are met. “B” denotes linkage disequilibrium between AdipoQ variants and those of a second gene regulating adiposity—and therefore insulin sensitivity, which would violate the assumption that AdipoQ variants are not susceptible to confounders that may influence the association between circulating adiponectin and outcome. Linkage disequilibrium with such a locus is not known to exist. “C” denotes gene × adiposity interaction as a potential violation of the assumption that AdipoQ is independent of environmental influences, which could bias the IV estimate of adiponectin’s effect on insulin sensitivity; however, how such an interaction would explain the negative correlation between adiponectin-raising AdipoQ SNPs in the current study is unclear. “D” denotes hypothetical suppression of adiponectin production by hyperinsulinemia acting through signaling pathways separate from those directly affecting glucose transport, an instance of reverse causality that would bias the association between the IV estimate of effect of adiponectin on insulin sensitivity. Once again, this would not readily explain the negative correlation reported in the study by Gao et al. between adiponectin-raising AdipoQ variants and adiposity.
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