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(Stroke. 2008;39:1952.)
© 2008 American Heart Association, Inc.

Original Contributions

Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain

The Cardiovascular Health Study

Myriam Fornage, PhD; Y. Aron Chiang, MS; Ellen S. O'Meara, PhD; Bruce M. Psaty, MD, PhD; Alexander P. Reiner, PhD; David S. Siscovick, MD, MPH; Russell P. Tracy, PhD W.T. Longstreth, Jr, MD, MPH

From the Brown Foundation Institute of Molecular Medicine (M.F., Y.A.C.), University of Texas Health Science Center at Houston; the Departments of Biostatistics (E.S.O.), Medicine (B.M.P.), Health Services (B.M.P.), and Epidemiology (B.M.P., A.P.R., D.S.S.), the Cardiovascular Health Research Unit (B.M.P., D.S.S.), and the Department of Neurology (W.T.L.), University of Washington, Seattle; the Center for Health Studies (B.M.P.), Group Health, Seattle, Wash; and the Departments of Medicine and Pathology (R.P.T.), University of Vermont, Burlington.

Correspondence to Myriam Fornage, PhD, Brown Foundation Institute of Molecular Medicine, 1825 Pressler Street, Suite 530.G, Houston, TX 77030. E-mail myriam.fornage{at}uth.tmc.edu

Background and Purpose— To clarify the role of inflammation in the pathogenesis of small vessel disease of the brain, we investigated the association between common variation in the C-reactive protein (CRP) and interleukin (IL)-6 genes, plasma CRP and IL6 levels, and presence of MRI-defined white matter lesions (WML) and brain infarcts (BI) in elderly participants of the Cardiovascular Health Study.

Methods— Tag single nucleotide polymorphisms (SNPs) in the CRP and IL6 genes were selected from the SeattleSNPs database. In cross-sectional analyses, logistic regression models adjusting for known cardiovascular disease risk factors were constructed to assess the associations of plasma CRP and IL6 levels and common CRP and IL6 gene haplotypes with presence of WML or BI in Blacks (n=532) and Whites (n=2905).

Results— Plasma IL6 and CRP levels were associated with presence of WML and BI in both races. In Whites, common haplotypes of the IL6 gene were significantly associated with WML and BI. The common haplotype tagged by the –174G/C promoter polymorphism was associated with an increased risk of WML (OR=1.14; 95% CI: [1.02; 1.28]). The common haplotype tagged by the –572G/C promoter polymorphism was associated with an increased risk of BI (OR=1.57; 95% CI: [1.15; 2.14]). Significant associations were lacking for WML or BI with IL6 gene variation in Blacks, or with CRP gene variation in either race.

Conclusions— This study provides evidence of a genetic basis underlying the relationship between plasma biomarkers of inflammation and small vessel disease of the brain. Further studies to elucidate the specific role of IL6 in disease pathogenesis are warranted.

Key Words: brain infarction • cerebrovascular disease • epidemiology • genetics • inflammation • leukoaraiosis • risk factors • white matter disease