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

<jats:sec xml:lang="en"> <jats:title>Background</jats:title> <jats:p xml:lang="en"> Plasma adiponectin levels have previously been inversely associated with carotid intima‐media thickness ( <jats:styled-content style="fixed-case">IMT</jats:styled-content> ), 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 <jats:styled-content style="fixed-case">IMT</jats:styled-content> . </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Methods and Results</jats:title> <jats:p xml:lang="en"> Baseline plasma adiponectin concentration was tested for association with baseline <jats:styled-content style="fixed-case">IMT</jats:styled-content> , <jats:styled-content style="fixed-case">IMT</jats:styled-content> 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 <jats:styled-content style="fixed-case">IMT</jats:styled-content> after adjustment for established risk factors (β=−0.018, <jats:italic>P</jats:italic> &lt;0.001) in men but not in women (β=−0.006, <jats:italic>P</jats:italic> =0.185; <jats:italic>P</jats:italic> for interaction=0.061). Adiponectin levels were inversely associated with progression of mean common carotid <jats:styled-content style="fixed-case">IMT</jats:styled-content> in men (β=−0.0022, <jats:italic>P</jats:italic> =0.047), whereas no association was seen in women (0.0007, <jats:italic>P</jats:italic> =0.475; <jats:italic>P</jats:italic> for interaction=0.018). Moreover, we observed that adiponectin levels were inversely associated with coronary events in women (hazard ratio 0.57, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content> 0.37 to 0.87) but not in men (hazard ratio 0.82, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content> 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 <jats:styled-content style="fixed-case">IMT</jats:styled-content> in men (β=−0.0008, <jats:italic>P</jats:italic> =0.004) but not in women (β=−0.0003, <jats:italic>P</jats:italic> =0.522; <jats:italic>P</jats:italic> for interaction=0.007). </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Conclusions</jats:title> <jats:p xml:lang="en">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.</jats:p> </jats:sec>