title: Genetic and acquired inflammatory conditions are synergistically associated with early carotid atherosclerosis.
abstract: 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.
authors.affiliation: Centre for Clinical Neuroscience, Department of Cardiac and Vascular Sciences, St George's University of London, UK. hmarkus@sgul.ac.uk
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
authors.forename: Robyn
authors.initials: R
authors.lastname: Labrum
authors.forename: Steve
authors.initials: S
authors.lastname: Bevan
authors.forename: Markus
authors.initials: M
authors.lastname: Reindl
authors.forename: Georg
authors.initials: G
authors.lastname: Egger
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Wiedermann
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
authors.forename: Stefan
authors.initials: S
authors.lastname: Kiechl
authors.forename: Johann
authors.initials: J
authors.lastname: Willeit
mesh_terms: 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
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D012795:Sialoglycoproteins