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Genetic Influences of Adiponectin on Insulin Resistance, Type 2 Diabetes, and Cardiovascular Disease

¹ Research Unit of Diabetology and Endocrinology, Scientific Institute "Casa Sollievo della Sofferenza," San Giovanni Rotondo, Italy
² Department of Clinical Sciences, University La Sapienza, Rome, Italy
³ Research Division, Joslin Diabetes Center, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Alessandro Doria, MD, PhD, MPH, Section on Genetics & Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: alessandro.doria{at}joslin.harvard.edu; or to Claudia Menzaghi, PhD, Research Unit of DiabetologyEndocrinology, Scientific Institute "Casa Sollievo della Sofferenza," Viale Padre Pio, 71013 San Giovanni Rotondo (FG), Italy. E-mail: c.menzaghi{at}operapadrepio.it

Abbreviations: AdipoR1, adiponectin receptor 1; AdipoR2, adiponectin receptor 2; CAD, coronary artery disease; HOMA_IR, homeostasis model assessment of insulin resistance; LD, linkage disequilibrium; SNP, single nucleotide polymorphism; TZD, thiazolidinedione; UTR, untranslated region; WMD, weighted mean difference

Recent evidence points to molecules secreted by the adipose tissue, or adipokines, as possible links between increased adipose mass and metabolic abnormalities. Among these molecules, adiponectin has drawn much attention because of its insulin-sensitizing and antiatherogenic actions, suggesting that genetic deficits in its production or action may contribute to insulin resistance and coronary artery disease (CAD). A meta-analysis of the data published to date supports this hypothesis. Two independent effects, corresponding to the two linkage disequilibrium blocks that can be identified at the adiponectin locus, appear to be present. In the 5' block, the g.–11391GA variant has a modest but significant effect on adiponectinemia, with a mean difference between genotypes of 1.64 ng/ml (95% CI 0.88–2.41). In the 3' block, the g.+276GT variant is a strong determinant of insulin resistance and CAD, with minor allele homozygotes having a lower homeostasis model assessment of insulin resistance (HOMA_IR) index (–0.36 units, 95% CI 0.24–0.47) and a lower cardiovascular risk (odds ratio 0.55, 95% CI 0.38–0.80) than carriers of other genotypes. No consistent effect on BMI or risk of type 2 diabetes is evident. Polymorphisms in the genes coding for the adiponectin receptors may also influence the risk of insulin resistance and CAD, but data on these genes are still too sparse to draw firm conclusions. In summary, the studies published to date indicate that polymorphisms at the adiponectin locus are indeed predictors of circulating adiponectin levels, insulin sensitivity, and atherosclerosis, highlighting the pivotal role of this adipokine in the modulation of metabolism and atherogenesis.

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