Linkage of large-vessel carotid atherosclerotic stroke to inflammatory genes via a systematic screen.
BACKGROUND
Inflammatory cytokines including the IL-1 family, TNF-alpha and IL-6 mediate the formation of thrombosis on the luminal surface of atherosclerotic plaques. Gene polymorphisms that regulate these cytokines' expression may explain part of the variation in susceptibility to stroke in patients with carotid atherosclerosis. The aim of this study was to evaluate the role of single-nucleotide polymorphisms (SNPs) and haplotypes in inflammatory genes as they relate to symptomatic carotid atherosclerosis.


METHODS
The study included 95 subjects with symptomatic (transient ischaemic attacks or stroke) and 113 subjects with asymptomatic carotid atherosclerotic disease. A panel of evenly spaced SNPs including previously reported functionally significant polymorphisms were genotyped for IL-1beta (10 SNPs), IL-1alpha (nine SNPs), IL-1RN (11 SNPs), IL-6 (seven SNPs) and TNF-alpha and TNF-beta (seven SNPs).


RESULTS
Using single SNP analysis, IL-1RN rs315934 (P=0.025), IL-1RN rs315946 (P=0.042), IL-1RN rs315921 (P=0.035), IL-6 rs1180243 (P=0.018) and IL-1alpha rs2071373 (P=0.025) were associated with decreased odds of symptomatic carotid disease. Additionally, two diplotypes of the IL-1RN gene (P=0.023 and 0.0064) and one diplotype in the IL-1alpha gene (P=0.02) were associated with a protective affect from cerebral ischaemic events. Logistic analysis for interaction of the protective SNPs reveals an additive effect of all SNP pair combinations.


CONCLUSIONS
These results suggest that genetic polymorphisms in proinflammatory genes may contribute to interindividual differences in the development of symptomatic carotid atherosclerotic disease.
Belfer
Inna
I
National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD, USA.
Wu
Tianxia
T
Hipp
Heather
H
Walter
Joan
J
Scully
Michele
M
Nyquist
Paul A
PA
Bollettino
Antonella
A
Goldman
David
D
Max
Mitchell B
MB
DeGraba
Thomas J
TJ
D000368:Aged; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology*; D002339:Carotid Arteries / Q000473:pathology*; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D007375:Interleukin-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007958:Leukocyte Count; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D020521:Stroke / Q000235:genetics* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D005819:Genetic Markers; D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D004247:DNA