Sex-Specific Effects of Adiponectin on Carotid Intima-Media Thickness and Incident Cardiovascular Disease

Abstract

Background-Plasma adiponectin levels have previously been inversely associated with carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis. In this study, we used a sex-stratified Mendelian randomization approach to investigate whether adiponectin has a causal protective influence on IMT. Methods and Results-Baseline plasma adiponectin concentrationwas tested for association with baseline IMT, IMT progression over 30 months, and occurrence of cardiovascular events within 3 years in 3430 participants (women, n=1777; men, n=1653) with high cardiovascular risk but no prevalent disease. Plasma adiponectin levels were inversely associated with baseline mean bifurcation IMT after adjustment for established risk factors (beta=-0.018, P<0.001) in men but not in women (beta=-0.006, P=0.185; P for interaction=0.061). Adiponectin levels were inversely associated with progression of mean common carotid IMT in men (beta=-0.0022, P=0.047), whereas no association was seen in women (0.0007, P=0.475; P for interaction=0.018). Moreover, we observed that adiponectin levels were inversely associated with coronary events in women (hazard ratio 0.57, 95% CI 0.37 to 0.87) but not in men (hazard ratio 0.82,95% CI0.54 to 1.25). Agenescore of adiponectin-raisingalleles in6loci, reported recently inalarge multi-ethnic metaanalysis, was inversely associated with baseline mean bifurcation IMT in men (beta=-0.0008, P=0.004) but not in women (beta=-0.0003, P=0.522; P for interaction=0.007). Conclusions-This report provides some evidence for adiponectin protecting against atherosclerosis, with effects being confined to men; however, compared with established cardiovascular risk factors, the effect of plasma adiponectin was modest. Further investigation involving mechanistic studies is warranted. ; Funding: IMPROVE was supported by the European Commission (Contract number: QLG1-CT-2002-00896), the Swedish Heart-Lung Foundation, the Swedish Research Council (projects 8691 and 0593), the Knut and Alice Wallenberg Foundation, the Foundation for Strategic Research, the Stockholm County Council (project 592229), the Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet and Stockholm County Council, the European Union Framework Programme 7 (FP7/2007-2013) for the Innovative Medicine Initiative under grant agreement no. IMI/115006 (the SUMMIT consortium), the Academy of Finland (Grant #110413), the British Heart Foundation (RG2008/08, RG2008/014) and the Italian Ministry of Health (Ricerca Corrente). The SNP Technology Platform is supported by Uppsala University, Uppsala University Hospital and the Swedish Research Council for Infrastructures. Persson is supported by the Stockholm County Council (clinical postdoctorial appointment). Strawbridge is supported by Swedish Heart-Lung Foundation (20120600), the Tore Nilsson, Gamla Tjanarinnor and Thurings foundations. Gertow acknowledges support from the Swedish Heart-Lung Foundation and Stiftelsen for Gamla Tjanarinnor. Sabater-Lleal is supported by the Swedish Heart-Lung Foundation (20130399), and acknowledges funding from Ake Wiberg and Tore Nilssons foundations. Sennblad acknowledges funding from the Magnus Bergvall Foundation and the Foundation for Old Servants. Rauramaa acknowledges the Ministry of Education and Culture in Finland. S.So. is supported by the Vasterbotten County Council (ALF) and the Swedish Heart and Lung Foundation. AGT is supported by TAMOP 4.2.4.A/1-11-1-2012-0001 National Excellence Program - research fellowship co-financed by the European Union and the European Social Fund. M.K. is supported by the UK Medical Research Council (K013351), the Economic and Social Research Council and the Academy of Finland. The University College London Genetics Institute supported S.Sh.