The association of SNPs in ADIPOQ, ADIPOR1, and ADIPOR2 with insulin sensitivity in a cohort of adolescents and their parents

Abstract

Few studies have examined the association of SNPs in the adiponectin (ADIPOQ) and adiponectin receptor 1 and 2 (ADIPOR1, ADIPOR2) genes with the euglycemic clamp, i.e. the gold standard measure of insulin sensitivity. The association of comprehensive tag SNPs in these genes with insulin sensitivity was examined in a cohort of adolescents and their parents. Probands and siblings (n = 441, mean age = 17.9 years) were recruited along with their parents (n = 262, mean age = 47.9 years).Typed SNPs included 21 SNPs in ADIPOQ, 7 SNPs in ADIPOR1, and 13 SNPs in ADIPOR2. Mixed model linear regression was used to test the association of SNPs with euglycemic-clamp derived insulin sensitivity. All analyses were stratified by race. After corrections to account for multiple testing and the linkage disequilibrium structure of the genes, one SNP in the ADIPOQ gene (rs822393) was significantly associated with insulin sensitivity in white subjects. In whites, six SNPs in ADIPOQ, one SNP in ADIPOR1 and one SNP in ADIPOR2 were associated with insulin sensitivity at the p < .05 level. In African Americans, two SNPs in ADIPOR1 were associated with insulin sensitivity at the p < .05 level. These results suggest that a variant in the ADIPOQ gene influences levels of insulin sensitivity and age may modify the effects of this variant. There are several other variants in ADIPOQ, ADIPOR1, and ADIPOR2 that may influence insulin sensitivity and these variants should be further investigated in other populations. KeywordsInsulin sensitivity; adiponectin; euglycemic clamp; SNP Adiponectin, an adipokine, is inversely related to both adiposity and many chronic disease risk factors, including insulin resistance. Adiponectin has been associated, cross-sectionally, with measures of adiposity (Shand et al. 2003;Weyer et al. 2001) and both cross-sectionally and longitudinally with euglycemic-clamp derived insulin sensitivity (Rasmussen-Torvik et al. In press;Stefan et al. 2002). Because of these relations, adiponectin may play a causal role in the association of obesity and insulin resistance.Previous studies have identified SNPs in the adiponectin gene (ADIPOQ) that appear to alter the transcription or activity of adiponectin (Menzaghi et al. 2007).Additional studies have identified SNPs in two receptors for adiponectin (ADIPOR1 and ADIPOR2) that may also (Damcott et al. 2005;Stefan et al. 2005).Few studies have examined the association of SNPs in these genes with the moderately heritable (RasmussenTorvik et al. 2007) gold standard measure of insulin sensitivity, the euglycemic clamp (Buzzetti et al. 2007;Kantartzis et al. 2006;Salmenniemi et al. 2005;Stefan et al. 2005;Ukkola et al. 2005;Vozarova de Courten et al. 2005) and only two other studies attempted to use tag SNPs to capture variation throughout the entire gene (Hara et al. 2005;Vozarova de Courten et al. 2005).Additionally, most previous studies have been conducted in middle-aged or older populations. In this study, the association of tag SNPs (selected using the International Hap...

Adiponectin gene polymorphisms (T45G and G276T), adiponectin levels and risk for metabolic diseases in an Arab population

“…The adiponectin gene resides within the susceptibility loci for T2DM and insulin resistance syndrome on chromosome 3q27 (Kissebah et al, 2000;Vionnet et al, 2000). Accordingly, several SNPs have been described in the adiponectin gene and are associated with metabolic phenotypes including obesity, T2DM and insulin resistance (Stumvoll et al, 2002;Bouatia-Naji et al, 2006;Hara et al, 2002;Hivert et al, 2008;Tso et al, 2006;Schwarz et al, 2006;Szopa et al, 2009;Jang et al, 2008;Pérez-Martínez et al, 2008;Rasmussen-Torvik et al, 2009;Melistas et al, 2009). Among all, T45G and G276T SNPs of adiponectin gene are widely studied in relation to their associations with the metabolic phenotypes.…”

“…Consistent with the association at protein levels, genetic studies have also demonstrated a link between adiponectin gene and the metabolic phenotypes. Several single nucleotide polymorphisms (SNPs) are described in the adiponectin gene and were found to be associated with obesity (Stumvoll et al, 2002;BouatiaNaji et al, 2006), type 2 diabetes mellitus Hivert et al, 2008;Tso et al, 2006;Schwarz et al, 2006;Szopa et al, 2009) and insulin resistance (Stumvoll et al, 2002;Jang et al, 2008;Pérez-Martínez et al, 2008;Rasmussen-Torvik et al, 2009;Melistas et al, 2009). Although it should be noted that other studies have reported a lack of such an association; with conflicting reports observed, at times, within the same ethnicity (Lee et al, 2005;Vasseur et al, 2002;Populaire et al, 2003;Gu et al, 2004;Vozarova de Courten et al, 2005).…”

Association of adiponectin gene polymorphisms and additional gene-gene interaction with nonalcoholic fatty liver disease in the Chinese Han population

“…Ramya et al [24] conducted a study in the a South Indian population and found a genetic association of rs822393 (-4522 C/T) variants of the adiponectin gene with type 2 diabetes mellitus (T2DM), obesity, and the serum adiponectin level. Rasmussen-Torvik et al [25] suggested that rs822393 was significantly associated with insulin sensitivity in white subjects. Wassel et al [26] indicated that ADIPOQ SNP rs822393 was strongly associated with serum adiponectin concentrations in white subjects.…”

Genetic Architecture of Plasma Adiponectin Overlaps With the Genetics of Metabolic Syndrome–Related Traits

“…Adiponectin is secreted and present in plasma in various multimeric forms, for which the biological significance remains to be determined. Rasmussen-Torvik et al (5) showed that binding of adiponectin to adiponectin receptors (ADIPOR1 and ADIPOR2) in mice results in increased AMP-activated protein kinase activity and peroxisome proliferator–activated receptor-α activity. In humans, both receptors are expressed mainly in skeletal muscle and adiponectin could thus play a role in energy metabolism.…”

“…Furthermore, it is not known whether the genetics of plasma adiponectin overlap with the genetics of body weight and insulin sensitivity/diabetes or other individual components of the metabolic syndrome. Several studies showed convincing association of genetic variants near and in the promoter region of the ADIPOQ gene with plasma adiponectin and type 2 diabetes or type 2 diabetes–related traits (5,9,10). …”