Adiponectin is a protein secreted by adipocytes that modulates insulin action. To assess whether variants of this gene contribute to the prevalence of insulin resistance in Caucasians, we genotyped 413 nondiabetic individuals for two single nucleotide polymorphisms (SNPs) at this locus. The two SNPs (45T3 G and 276G3 T) were chosen because of their association with type 2 diabetes in Japanese. Whereas each polymorphism was significantly associated with some correlate of insulin resistance, the haplotype defined by the two together was strongly associated with many components of the insulin resistance syndrome. Homozygotes for the risk haplotype had higher body weight (P ؍ 0.03), waist circumference (P ؍ 0.004), systolic (P ؍ 0.01) and diastolic (P ؍ 0.003) blood pressure, fasting glucose (P ؍ 0.02) and insulin (P ؍ 0.005) levels, homeostasis model assessment (HOMA) for insulin resistance (P ؍ 0.003), and total to HDL cholesterol ratio (P ؍ 0.01). Homozygotes also had significantly lower plasma levels of adiponectin (P ؍ 0.03), independent of sex, age, and body weight. In an independent study group of 614 Caucasians, including 310 with type 2 diabetes, the risk haplotype was confirmed to be associated with increased body weight (P ؍ 0.03) but not with type 2 diabetes per se. We conclude that variability at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome, but given the nature of the two SNPs, the risk haplotype is most probably a marker in linkage disequilibrium with an as yet unidentified polymorphism that affects plasma adiponectin levels and insulin sensitivity. Diabetes 51: 2306 -2312, 2002
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.؊11391G3 A 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. O ur view of adipose tissue has undergone dramatic changes over the past 15 years. Previously believed to be a mere energy depot, adipose tissue is now considered a major endocrine organ regulating whole-body metabolism as well as inflammatory and immune responses (1,2). These actions are mediated by a number of molecules-collectively known as adipokines-that are secreted by adipocytes and act in an autocrine, paracrine, or endocrine fashion, adapting metabolic fluxes to the amount of stored energy (1,2). The discovery of such endocrine function of the adipose tissue has prompted the hypothesis that a genetic dysregulation of the adipokine network may contribute to the pathogenesis of insulin resistance and related disorders such as type 2 diabetes and cardiovascular disease. Of all the molecules that have been shown to be produced by the adipose tissue, adiponectin has drawn special attention, largely due to its effects on both insulin sensitivity and inflammation, and the fact that its expression and serum levels can be modulated by peroxisome proliferatoractivated receptor (PPAR)-␥ agonists drugs (Fig. 1). In this article, we will review the evidence that has been thus far gathered on the role of genetic variants in the adiponectin and adiponectin receptors genes as modulators of adiponectin-circulating levels and susceptibility to insulin resistance traits. We will also discuss the directions in which research on this topic is heading. ADIPONECTIN: A SALUTARY ADIPOKINEAdiponectin, also known as adipocyte complement-related protein 30 (Acrp30), gelatin-binding protein 28 (Gbp28), adipose most abundant transcript 1(apM1), or AdipoQ, is exclusively produced by adipocytes (3-6). It is abundantly present in serum, where it circulates in two higher-order forms: a low-molecular weight dimer of trimers and a larger high-molecular weight complex of 12-18 subunits (7). Serum levels are 15% higher in women than in men (8). Data from both animal and human studies indicate that adiponectin has insulin-enhancing as well as anti-inflammatory actions (rev. in 9). Adiponectin levels are markedly reduced in obese/diabetic mice, and injection of the adiponectin globular domain to these animals ameliorates ...
CD36 is a class B scavenger receptor recognizing a variety of ligands including long-chain fatty acids and modified LDL. We investigated whether genetic variability at this locus is a determinant of free fatty acid (FFA) plasma levels and risk of coronary artery disease (CAD) in Caucasians. Typing of 21 polymorphic markers, evenly spanning the CD36 gene, revealed two linkage disequilibrium (LD) blocks that could be tagged by five polymorphisms (-33137A>G, -31118G>A, 25444G>A, 27645del>ins and 30294G>C). In 585 non-diabetic individuals of Caucasian origin, the 30294G>C polymorphism was significantly associated with FFA levels (P = 0.02)--an effect that was especially visible among men (P = 0.009). A similar association was observed in this gender at -33137 (P = 0.008) and -31118 (P = 0.028). When the five tag polymorphisms were considered together, men carrying the AGGIG haplotype had 31% higher FFA (P = 0.0002) and 20% higher triglycerides (P = 0.025) than non-carriers. The same haplotype was associated with increased risk of CAD in 197 type 2 diabetic individuals from the US (OR = 2.3, 95% CI 1.2-4.2). A similar tendency was observed in a group of 321 type 2 diabetic individuals from Italy (OR = 1.4, 0.9-2.3), resulting in an overall relative risk of 1.6 (1.1-2.3, P = 0.015) in the two populations considered together. By targeted resequencing, we identified a common variant in the CD36 promoter that is in strong LD with the AGGIG haplotype and could be partly responsible for these findings. In conclusion, this comprehensive study of CD36 variability indicates that the common polymorphisms at this locus modulate lipid metabolism and cardiovascular risk in Caucasians.
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