Abstract
Adiponectin, an adipocyte-derived protein, is an essential modulator of insulin sensitivity and several studies suggest an important role of adiponectin in the processes leading to atherosclerosis, thus indicating the adiponectin gene as a potential candidate for coronary artery disease (CAD). In the present study we have studied the association between two single nucleotide polymorphisms (SNPs) (+45T>G and +276 G>T) of the adiponectin gene and CAD, looking also into the possible influence of these SNPs on adiponectin plasma levels. The SNPs were analysed in a first cohort of 595 subjects, 325 with CAD and 270 matched controls. We observed a significant association (p<0.001) between the SNP +276G>T in the adiponectin gene and CAD. In multivariate analysis, carriers of the +276G>T SNP had an odds ratio (OR) for CAD of 4.99 (p<0.0007). A strong interaction between the +276G>T SNP and age was also present (OR, 1.03; p<0.0001). The increase in CAD risk was most evident among individuals with early-onset CAD (age ≤50 years), whereas in older CAD subjects other factors, and not the adiponectin SNP, were the major determinants. Furthermore, in CAD subjects with early-onset disease this SNP was also a significant determinant of lower levels of serum adiponectin levels. This association resulted independent from the other variables known to be associated with CAD in our population, including sex, body mass index, high-density lipoprotein and Homeostasis Model Assessment for insulin resistance. To confirm the results the +276G>T SNP was analysed in a second cohort of CAD and controls. The difference between CAD and controls in the +276G>T SNP frequencies showed a similar trend as before, although not significant. The combination of the two cohorts (1,046 subjects: 580 CAD and 466 controls) showed a statistically significant association, particularly in CAD subjects with early-onset of disease. In addition, we confirmed that in younger CAD subjects the SNP was a significant determinant of lower levels of adiponectin. In view of these results, it could be speculated that the adiponectin gene variant, or a mutation in linkage with it, determines lower adiponectin gene expression, causing in turn an increased risk to develop insulin resistance, atherosclerosis and cardiovascular disease. The significant association of the adiponectin gene in subjects with early-onset CAD also suggests that that genetic factors for late-onset diseases may exert a greater influence in younger persons, when other risk factors are not as prevalent as in older age groups.
Similar content being viewed by others
References
Okamoto Y, Arita Y, Nishida M, Muraguchi M, Ouchi N, Takahashi M, Igura T, Inui Y, Kihara S, Nakamura T, Yamashita S, Miyagawa J, Funahashi T, Matsuzawa Y (2000) An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls. Horm Metab Res 32(2):47–50
Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tatarami PA (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935
Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y (2000) Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20(6):1595–1599
Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Funahashi T, Matsuzawa Y, Osaka CAD Study Group (2003) Coronary artery disease. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 23(1):85–89
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(2):239–243
Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, Kamon J, Satoh H, Yano W, Froguel P, Nagai R, Kimura S, Kadowaki T, Noda T (2002) Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 277(29):25863–25866
Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, Kumada M, Hotta K, Nishida M, Takahashi M, Nakamura T, Shimomura I, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y (2002) Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation 105(24):2893–2898
Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y (2000) Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96(5):1723–1732
Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, Ishigami M, Kuriyama H, Ishida K, Nishizawa H, Hotta K, Muraguchi M, Ohmoto Y, Yamashita S, Funahashi T, Matsuzawa Y (2001) Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 103(8):1057–1063
Haluzik M, Parizkova J, Haluzik MM (2004) Adiponectin and its role in the obesity-induced insulin resistance and related complications. Physiol Res 53(2):123–129
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(8):941–946
Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y (2002) Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 8(7):731–737
Kondo H, Shimomura I, Matsukawa Y, Kumada M, Takahashi M, Matsuda M, Ouchi N, Kihara S, Kawamoto T, Sumitsuji S, Funahashi T, Matsuzawa Y (2002) Association of adiponectin mutation with type 2 diabetes: a candidate gene for the insulin resistance syndrome. Diabetes 51(7):2325–2328
Menzaghi C, Ercolino T, Di Paola R, Berg AH, Warram JH, Scherer PE, Trischitta V, Doria A (2002) A haplotype in the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome. Diabetes 51(7):2306–2312
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(1):37–41
Vasseur F, Helbecque N, Dina C, Lobbens S, Delannoy V, Gaget S, Boutin P, Vaxillaire M, Lepretre F, Dupont S, Hara K, Clement K, Bihain B, Kadowaki T, Froguel P (2002) Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians. Hum Mol Genet 11(21):2607–2614
Filippi E, Sentinelli F, Trischitta V, Romeo S, Arca M, Leonetti F, Di Mario U, Baroni MG (2004) Association of the human adiponectin gene and insulin resistance. Eur J Hum Genet 12(3):199–205
Hu FB, Doria A, Li T, Meigs JB, Liu S, Memisoglu A, Hunter D, Manson JE (2004) Genetic variation at the adiponectin locus and risk of type 2 diabetes in women. Diabetes 53(1):209–213
Hara K, Boutin P, Mori Y, Tobe K, Dina C, Yasuda K, Yamauchi T, Otabe S, Okada T, Eto K, Kadowaki H, Hagura R, Akanuma Y, Yazaki Y, Nagai R, Taniyama M, Matsubara K, Yoda M, Nakano Y, Tomita M, Kimura S, Ito C, Froguel P, Kadowaki T (2002) Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes 51(2):536–540
Ohashi K, Ouchi N, Kihara S, Funahashi T, Nakamura T, Sumitsuji S, Kawamoto T, Matsumoto S, Nagaretani H, Kumada M, Okamoto Y, Nishizawa H, Kishida K, Maeda N, Hiraoka H, Iwashima Y, Ishikawa K, Ohishi M, Katsuya T, Rakugi H, Ogihara T, Matsuzawa Y (2004) Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease. J Am Coll Cardiol 43(7):1195–1200
Rose GA, Blackburn H (1968) Cardiovascular survey methods, 1st edn. No. 56. World Health Organization, Geneva
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2001) Diabetes Care 24(Suppl 1):S5
Definition, diagnosis and classification of diabetes mellitus and its complications (1999) Report of a WHO Consultation
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
Lewontin RC (1984) The interaction of selection and linkage 1. General considerations: heterotic models. Genetics 49:49–67
Rissanen AM (1979) Familial occurrence of coronary artery disease: effect of age at diagnosis. Am J Cardiol 44:60–66
Marenberg ME, Risch N, Berkman LF, Floderus B, De Faire U (1994) Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 330:1041–1046
Yamamoto Y, Hirose H, Saito I, Tomita M, Taniyama M, Matsubara K, Okazaki Y, Ishii T, Nishikai K, Saruta T (2002) Correlation of the adipocyte-derived protein adiponectin with insulin resistance index and serum high-density lipoprotein-cholesterol, independent of body mass index, in the Japanese population. Clin Sci (Lond) 103(2):137–142
Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB (2004) Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 291(14):1730–1737
Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, Terasaka N, Inaba T, Funahashi T, Matsuzawa Y (2002) Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106(22):2767–2770
Matsuda M, Shimomura I, Sata M, Arita Y, Nishida M, Maeda N, Kumada M, Okamoto Y, Nagaretani H, Nishizawa H, Kishida K, Komuro R, Ouchi N, Kihara S, Nagai R, Funahashi T, Matsuzawa Y (2002) Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis. J Biol Chem 277(40):37487–37491
Fernandez-Real JM, Castro A, Vazquez G, Casamitjana R, Lopez-Bermejo A, Penarroja G, Ricart W (2004) Adiponectin is associated with vascular function independent of insulin sensitivity. Diabetes Care 27(3):739–745
Yang WS, Tsou PL, Lee WJ, Tseng DL, Chen CL, Peng CC, Lee KC, Chen MJ, Huang CJ, Tai TY, Chuang LM (2003) Allele-specific differential expression of a common adiponectin gene polymorphism related to obesity. J Mol Med 81(7):428–434
Acknowledgements
Financial support to this work was provided by the Faculty of Medicine (grant C26F022871) of the University of Rome “La Sapienza”, by the Italian Ministry of the University and Scientific Research (COFIN 2003), and by the Ministry of Health (grant RF2003) all to M.G. Baroni. We wish to thank Dr. Paolo Rubino and Dr. Tullio Tesorio, Cardiac Catheterisation Unit, Casa di Cura Montevergine di Mercogliano (AV), for their participation in the study
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Filippi, E., Sentinelli, F., Romeo, S. et al. The adiponectin gene SNP+276G>T associates with early-onset coronary artery disease and with lower levels of adiponectin in younger coronary artery disease patients (age ≤50 years). J Mol Med 83, 711–719 (2005). https://doi.org/10.1007/s00109-005-0667-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-005-0667-z