Published Online
on July 27, 2006

A more recent version of this article appeared on September 1, 2006

This Article Full Text (PDF) All Versions of this Article: 37/9/2253    most recent 01.STR.0000236637.72124.3fv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Markus, H. S. Articles by Willeit, J. Search for Related Content PubMed PubMed Citation Articles by Markus, H. S. Articles by Willeit, J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Medline Plus Health Information Carotid Artery Disease Smoking Related Collections Genetics of cardiovascular disease Glucose intolerance Pathophysiology Risk Factors Carotid Stenosis Genetics of Stroke Risk Factors for Stroke

Submitted on January 4, 2006
Revised on March 24, 2006
Accepted on March 28, 2006

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; and 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.

^* To whom correspondence should be addressed. 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

This article has been cited by other articles:

				M. K. Ohman, Y. Shen, C. I. Obimba, A. P. Wright, M. Warnock, D. A. Lawrence, and D. T. Eitzman Visceral Adipose Tissue Inflammation Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, February 12, 2008; 117(6): 798 - 805. [Abstract] [Full Text] [PDF]

				C. Armstrong, S. Abilleira, M. Sitzer, H. S. Markus, and S. Bevan Polymorphisms in MMP Family and TIMP Genes and Carotid Artery Intima-Media Thickness Stroke, November 1, 2007; 38(11): 2895 - 2899. [Abstract] [Full Text] [PDF]

				B. Coll, S. Parra, C. Alonso-Villaverde, G. Aragones, M. Montero, J. Camps, J. Joven, and L. Masana The Role of Immunity and Inflammation in the Progression of Atherosclerosis in Patients With HIV Infection Stroke, September 1, 2007; 38(9): 2477 - 2484. [Abstract] [Full Text] [PDF]