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(Stroke. 2006;37:2253.)
© 2006 American Heart Association, Inc.

Original Contributions

Genetic and Acquired Inflammatory Conditions Are Synergistically Associated With Early Carotid Atherosclerosis

Hugh S. Markus, DM, FRCP; Robyn Labrum, PhD; Steve Bevan, PhD; Markus Reindl, MD; Georg Egger, MD; Christian J. Wiedermann, MD; Qingbo Xu, PhD; Stefan Kiechl, MD Johann Willeit, MD

From the Centre for Clinical Neuroscience (H.S.M., R.L., S.B.) and John Parker Chair of Vascular Biology (Q.X.), Department of Cardiac and Vascular Sciences, St George’s University of London, UK; the Department of Neurology (M.R., S.K., J.W.), Innsbruck Medical University, Innsbruck, Austria; the Department of Internal Medicine (C.J.W.), Innsbruck Medical University, Innsbruck, Austria; and the Department of Internal Medicine (G.E.), Bruneck Hospital, Bruneck, Italy.

Correspondence to Professor Hugh Markus, Centre for Clinical Neuroscience, St George’s University of London, London, SW17 ORE. E-mail hmarkus{at}sgul.ac.uk

Background and Purpose— If chronic inflammation plays a causal role in atherogenesis, individuals with proinflammatory gene variants would be expected to develop more atherosclerosis. We recently found a synergistic association between 3 functional proinflammatory gene polymorphisms/haplotypes and smoking on carotid intima-media thickness (IMT). We replicated this finding in a second large population and extended the analysis by inclusion of other inflammatory conditions (chronic infection and obesity/abnormal glucose tolerance).

Methods— Common carotid and femoral artery IMT was determined in the Bruneck Study population (n=810). Proinflammatory variants were determined in 3 genes (IL-6 [–174C, –572G, –597A haplotype], IL-1–receptor antagonist [VNTR *2], and endotoxin receptor CD-14 [–159C]).

Results— There was a significant relationship between gene-variant score and carotid IMT: age- and sex-adjusted mean IMT in subjects with 0, 1, and 2 gene variants was 936, 987 and 1047 µm, respectively (P=0.001), and synergistic effects of gene-variant score and smoking on IMT measurements (P=0.040). Analogous findings were obtained for obesity/abnormal glucose tolerance and chronic infection. Interactive effects of gene-variant score and a risk factor score composed of the acquired inflammatory conditions were highly significant (P<0.001 each). Results were similar for femoral artery IMT.

Conclusions— These results provide support for a causal role of inflammation in carotid atherosclerosis, and emphasize the importance of gene-gene and gene-environment interactions in this pathogenic pathway. This may help to explain the substantial variability of disease expression in subjects with proinflammatory risk factors such as smoking, diabetes and chronic infection.

Key Words: atherosclerosis • carotid artery • genetics • inflammation • risk factors

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