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

Jonas Persson, Rona J. Strawbridge, Olga McLeod, Karl Gertow, Angela Silveira, Damiano Baldassarre, Natalie Van Zuydam, Sonia Shah, Cristiano Fava, Stefan Gustafsson, Fabrizio Veglia, Bengt Sennblad, Malin Larsson, Maria Sabater‐Lleal, Karin Leander, Bruna Gigante, Adam Tabak, Mika Kivimaki, Jussi Kauhanen, Rainer Rauramaa, Andries J. Smit, Elmo Mannarino, Philippe Giral, Steve E. Humphries, Elena Tremoli, Ulf de Faire, Lars Lind, Erik Ingelsson, Bo Hedblad, Olle Melander, Meena Kumari, Aroon Hingorani, Andrew D. Morris, Colin N. A. Palmer, Pia Lundman, John Öhrvik, Stefan Söderberg, Anders Hamsten, the IMPROVE Study Group

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. Baseline plasma adiponectin concentration was 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 (β=-0.018, P<0.001) in men but not in women (β=-0.006, P=0.185; P for interaction=0.061). Adiponectin levels were inversely associated with progression of mean common carotid IMT in men (β=-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% CI 0.54 to 1.25). A gene score of adiponectin-raising alleles in 6 loci, reported recently in a large multi-ethnic meta-analysis, was inversely associated with baseline mean bifurcation IMT in men (β=-0.0008, P=0.004) but not in women (β=-0.0003, P=0.522; P for interaction=0.007). 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.