Genetic variability on adiponectin gene affects myocardial infarction risk: The role of endothelial dysfunction Alexios S. Antonopoulos 1 , Dimitris Tousoulis ⁎ , 1 , Charalambos Antoniades, Antigoni Miliou, George Hatzis, Nikolaos Papageorgiou, Michalis Demosthenous, Constantinos Tentolouris, Christodoulos Stefanadis 1st Cardiology Department, Hippokration Hospital, Athens Medical School, Greece abstract article info Article history: Received 25 April 2012 Received in revised form 20 July 2012 Accepted 15 September 2012 Available online 4 October 2012 Keywords: Adiponectin Myocardial infarction Endothelial function rs1501299 rs2241766 Background: Adiponectin is an adipokine with an important role in cardiovascular system conferring anti-inflammatory and anti-atherogenic effects. Two common single nucleotide polymorphisms (SNP) on adiponectin gene, rs2241766 and rs1501299, have been associated with insulin resistance and diabetes mellitus risk however their effects on cardiovascular risk remain unclear. We examined the impact of rs2241766 and rs1501299 on circulating adiponectin levels, endothelial function and cardiovascular disease risk. Methods: We recruited in total 594 subjects; 462 patients with angiographically confirmed coronary artery disease (CAD) and 132 controls matched for age and gender. rs2241766 and rs1501299 were genotyped by po- lymerase chain reaction and restriction endonuclease digestion. Serum adiponectin levels were determined by enzyme-linked immunosorbent assay. Endothelial function was assessed by the flow mediated dilatation (FMD) of the brachial artery. Results: rs2241766 had no effects on circulating adiponectin levels or FMD. In subjects without CAD, carriers of the T/T alleles at rs1501299 had lower adiponectin levels (p=0.001) and impaired endothelial function (p b 0.05). After multivariate adjustment none of the SNPs had any effect on CAD risk. However, carriers of the T allele at rs1501299 were at increased myocardial infarction (MI) risk, independently of classic risk factors (OR =2.558 [95%CI =1.587–4.123], p=0.0001). The number of T alleles in both SNPs was strongly associated with MI history (p=0.0001). Conclusions: rs1501299 polymorphism of adiponectin gene affects circulating adiponectin levels and endothelial function in subjects without CAD. Presence of the T variant at rs1501299 on adiponectin gene is independently associated with increased myocardial infarction risk. © 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Adipose tissue affects vascular function in a paracrine or endocrine manner via the release of bioactive molecules collectively called adipokines [1]. Adiponectin has been identified as an important adipokine with beneficial cardiovascular effects. In experimental studies adiponectin suppresses the expression of endothelial adhe- sion molecules [1] and attenuates vascular smooth muscle cell prolif- eration [2]. Ample evidence from further cell and animal studies have confirmed the powerful anti-atherogenic and anti-inflammatory ef- fects of adiponectin [3]. Despite the consistent findings of experimental data, clinical studies have yielded contradictory results. Adiponectin has been as- sociated with reduced or increased cardiovascular risk in humans, a finding that possibly highlights the complex mechanisms regulating its cardiovascular effects [4]. Moreover adiponectin synthesis in humans is dependent on underlying disease state; adiponectin ex- pression is down-regulated in obesity, while development of heart failure is associated with a striking increase in adiponectin plasma levels [3]. The role of genetic variability of adiponectin gene (ADIPOQ) on adiponectin expression has been investigated in several studies, which have yielded though conflicting results. Two common single nucleotide polymorphisms (SNPs) of ADIPOQ have drawn the most attention, rs2241766 (NC000003.11: g.186570892T>G, NG021140.1: g.15430T>G, NM004797.3:c.45T>G, NP004788.1: p.Gly15=.) and rs1501299 (NC000003.11:g.186571123G>T, NG021140.1: g.15661G>T, NM004797.3:c.214+62G>T). These two SNPs have been associated with changes in adiponectin circulating levels, insulin resistance and the risk for developing type 2 diabetes mellitus (OMIM citation for ADIPOQ: *6054410) [5,6], but their role in endothelial dysfunction and coronary atherosclerosis development remains unclear. In the present study we explored the impact of rs2241766 and rs1501299 on serum adiponectin levels, and we evaluated their potential International Journal of Cardiology 168 (2013) 326–330 ⁎ Corresponding author at: Athens University Medical School, S. Karagiorga 69, 16675, Glifada Athens, Greece. Tel.: +30 2107782446. E-mail address: drtousoulis@hotmail.com (D. Tousoulis). 1 Equally contributed. 0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.09.053 Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard