Published Online
on October 7, 2004

A more recent version of this article appeared on November 1, 2004

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Submitted on January 10, 2004
Accepted on August 11, 2004

Inflammatory Gene Load Is Associated With Enhanced Inflammation and Early Carotid Atherosclerosis in Smokers

Paula Jerrard-Dunne MRCPI^*; Matthias Sitzer MD; Paul Risley BSc; Alexandra Buehler MD; Stefan von Kegler MD; and Hugh S. Markus FRCP

From the Department of Clinical Neurosciences (P.J.-D., P.R., H.S.M.), St. Georges Hospital Medical School, London, UK; and the Department of Neurology (M.S., A.B., S.v.K.), Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.

^* To whom correspondence should be addressed. E-mail: pjerrard{at}sghms.ac.uk.

Background and Purpose--Smoking acts as a pro-inflammatory stimulus. Inflammation may provide a key mechanism by which smoking causes atherosclerosis. If so, then the degree to which an individual mounts an inflammatory response is likely to influence atherosclerosis severity. This study examined the impact of inflammatory gene polymorphisms and gene-smoking interactions on common carotid artery intima-media thickness (IMT), a measure of early atherosclerosis.

Methods--In a community population (n=1000), mean IMT was determined using ultrasound. This population was genotyped for 6 polymorphisms in 4 inflammatory genes: IL-6-174, IL-6-572, and IL-6-597; IL-1--31; IL-1 receptor antagonist VNTR and CD14-159. Serum IL-6 levels were measured in the first 500 subjects. Genotypes/haplotypes associated with higher IL-6 levels were designated "inflammatory haplotypes." A gene load score was calculated, in which 2 represented individuals homozygous for 2 inflammatory genotypes/haplotypes and 0 was homozygous for none.

Results--Increasing gene load of inflammatory genotypes was associated with a linear increase in serum IL-6 levels (P=0.018) and increased carotid artery IMT (P=0.003). There was a significant interaction between gene load and smoking status on carotid IMT (P for interaction=0.002). Specifically, in smokers, carriers of inflammatory haplotypes had significantly increased age- and sex-adjusted IMT (IL-6-174C/IL-6-572G/IL-6-597A, P=0.005; IL-1--31T/IL-1RN*2, P=0.04; CD14-159CC, P=0.028).

Conclusions--These findings support the hypothesis that inflammation and cytokine responses provide a key mechanism by which smoking causes atherogenesis. Secondly, they highlight the importance of gene-environment, and gene-gene-environment interactions in the pathogenesis of atherosclerosis.

Key words: arteriosclerosis • cigarette smoking • genetics • gene expression • inflammation

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