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 < 0.05 level. In African Americans, two SNPs in ADIPOR1 were associated with insulin sensitivity at the P < 0.05 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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Almasy L, Blangero J (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62:1198–1211
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265
Buzzetti R, Petrone A, Zavarella S, Zampetti S, Spoletini M, Potenziani S, Leto G, Osborn J, Leonetti F (2007) The glucose clamp reveals an association between adiponectin gene polymorphisms and insulin sensitivity in obese subjects. Int J Obes (Lond) 31:424–428
Cardon LR, Palmer LJ (2003) Population stratification and spurious allelic association. Lancet 361:598–604
Chen L, Xiang KS, Jia WP, Lu JX, Bao YQ, Lu HJ (2005) Serum adiponectin concentration in relation to body fat distribution and tissue insulin sensitivity in the glucose clamp study. Zhonghua Yi Xue Za Zhi 85:1456–1459
Damcott CM, Ott SH, Pollin TI, Reinhart LJ, Wang J, O’connell JR, Mitchell BD, Shuldiner AR (2005) Genetic variation in adiponectin receptor 1 and adiponectin receptor 2 is associated with type 2 diabetes in the old order Amish. Diabetes 54:2245–2250
Hara K, Horikoshi M, Kitazato H, Yamauchi T, Ito C, Noda M, Ohashi J, Froguel P, Tokunaga K, Nagai R, Kadowaki T (2005) Absence of an association between the polymorphisms in the genes encoding adiponectin receptors and type 2 diabetes. Diabetologia 48:1307–1314
Hivert MF, Manning AK, McAteer JB, Florez JC, Dupuis J, Fox CS, O’Donnell CJ, Cupples LA, Meigs JB (2008) Common variants in the adiponectin gene (ADIPOQ) associated with plasma adiponectin levels, type 2 diabetes, and diabetes-related quantitative traits: The Framingham offspring study. Diabetes. doi:10.2337/db08-0700
Kantartzis K, Fritsche A, Machicao F, Haring HU, Stefan N (2006) The -8503 G/A polymorphism of the adiponectin receptor 1 gene is associated with insulin sensitivity dependent on adiposity. Diabetes Care 29:464
Li J, Ji L (2005) Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity 95:221–227
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419
Menzaghi C, Trischitta V, Doria A (2007) Genetic influences of adiponectin on insulin resistance, type 2 diabetes, and cardiovascular disease. Diabetes 56:1198–1209
Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–769
Rasmussen-Torvik LJ, Pankow JS, Jacobs DR, Steffen LM, Moran AM, Steinberger J, Sinaiko AR (2007) Heritability and genetic correlations of insulin sensitivity measured by the euglycaemic clamp. Diabet Med 24:1286–1289
Rasmussen-Torvik LJ, Pankow JS, Jacobs Jr DR, Steinberger J, Moran A, Sinaiko AR (2008) Influence of waist on adiponectin and insulin sensitivity in adolescence. Obesity. doi:10.1038/oby.2008.482
Salmenniemi U, Zacharova J, Ruotsalainen E, Vauhkonen I, Pihlajamaki J, Kainulainen S, Punnonen K, Laakso M (2005) Association of adiponectin level and variants in the adiponectin gene with glucose metabolism, energy expenditure, and cytokines in offspring of type 2 diabetic patients. J Clin Endocrinol Metab 90:4216–4223
Shand BI, Scott RS, Elder PA, George PM (2003) Plasma adiponectin in overweight, nondiabetic individuals with or without insulin resistance. Diabetes Obes Metab 5:349–353
Sinaiko AR, Jacobs DR Jr, Steinberger J, Moran A, Luepker R, Rocchini AP, Prineas RJ (2001) Insulin resistance syndrome in childhood: associations of the euglycemic insulin clamp and fasting insulin with fatness and other risk factors. J Pediatr 139:700–707
Stefan N, Vozarova B, Funahashi T, Matsuzawa Y, Weyer C, Lindsay RS, Youngren JF, Havel PJ, Pratley RE, Bogardus C, Tataranni PA (2002) Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. Diabetes 51:1884–1888
Stefan N, Machicao F, Staiger H, Machann J, Schick F, Tschritter O, Spieth C, Weigert C, Fritsche A, Stumvoll M, Haring HU (2005) Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat. Diabetologia 48:2282–2291
Stumvoll M, Tschritter O, Fritsche A, Staiger H, Renn W, Weisser M, Machicao F, Haring H (2002) Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity: interaction with family history of type 2 diabetes. Diabetes 51:37–41
Thorisson GA, Smith AV, Krishnan L, Stein LD (2005) The international HapMap project web site. Genome Res 15:1592–1593
Tschritter O, Fritsche A, Thamer C, Haap M, Shirkavand F, Rahe S, Staiger H, Maerker E, Haring H, Stumvoll M (2003) Plasma adiponectin concentrations predict insulin sensitivity of both glucose and lipid metabolism. Diabetes 52:239–243
Ukkola O, Santaniemi M, Rankinen T, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bergman R, Kesaniemi YA, Bouchard C (2005) Adiponectin polymorphisms, adiposity and insulin metabolism: HERITAGE family study and Oulu diabetic study. Ann Med 37:141–150
Vozarova de Courten B, Hanson RL, Funahashi T, Lindsay RS, Matsuzawa Y, Tanaka S, Thameem F, Gruber JD, Froguel P, Wolford JK (2005) Common polymorphisms in the adiponectin gene ACDC are not associated with diabetes in Pima Indians. Diabetes 54:284–289
Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935
Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946
Yamauchi T, Kamon J, Waki H, Imai Y, Shimozawa N, Hioki K, Uchida S, Ito Y, Takakuwa K, Matsui J, Takata M, Eto K, Terauchi Y, Komeda K, Tsunoda M, Murakami K, Ohnishi Y, Naitoh T, Yamamura K, Ueyama Y, Froguel P, Kimura S, Nagai R, Kadowaki T (2003) Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem 278:2461–2468
Acknowledgments
This study was supported by grants HL52851 and M01RR00400 from the National Institutes of Health. LJR-T is supported by NHLBI training grant T32 HL07779.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Rasmussen-Torvik, L.J., Pankow, J.S., Jacobs, D.R. et al. The association of SNPs in ADIPOQ, ADIPOR1, and ADIPOR2 with insulin sensitivity in a cohort of adolescents and their parents. Hum Genet 125, 21–28 (2009). https://doi.org/10.1007/s00439-008-0595-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-008-0595-4