Genetic and acquired inflammatory conditions are synergistically associated with early carotid atherosclerosis.
OBJECTIVE
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 >or=2 gene variants was 936, 987 and 1047 microm, 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.
Markus
Hugh S
HS
Centre for Clinical Neuroscience, Department of Cardiac and Vascular Sciences, St George's University of London, UK. hmarkus@sgul.ac.uk
Labrum
Robyn
R
Bevan
Steve
S
Reindl
Markus
M
Egger
Georg
G
Wiedermann
Christian J
CJ
Xu
Qingbo
Q
Kiechl
Stefan
S
Willeit
Johann
J
D000368:Aged; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000209:etiology*; D017536:Carotid Artery, Common / Q000000981:diagnostic imaging; D005260:Female; D005263:Femoral Artery / Q000000981:diagnostic imaging; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000000981:diagnostic imaging / Q000209:etiology* / Q000235:genetics; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6 / Q000235:genetics; D002537:Intracranial Arteriosclerosis / Q000000981:diagnostic imaging / Q000209:etiology*; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D008297:Male; D008875:Middle Aged; D012795:Sialoglycoproteins / Q000235:genetics; D012907:Smoking / Q000009:adverse effects*; D017539:Tunica Intima / Q000000981:diagnostic imaging; D017540:Tunica Media / Q000000981:diagnostic imaging; D014463:Ultrasonography
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D012795:Sialoglycoproteins