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Prepublished online as a Blood First Edition Paper on August 15, 2002; DOI 10.1182/blood-2001-12-0306.
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Blood, 15 December 2002, Vol. 100, No. 13, pp. 4303-4309
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Variants in the VCAM1 gene and risk for symptomatic
stroke in sickle cell disease
James G. Taylor VI,
Delia C. Tang,
Sharon A. Savage,
Susan F. Leitman,
Seth I. Heller,
Graham R. Serjeant,
Griffin P. Rodgers, and
Stephen J. Chanock
From the Section on Genomic Variation, Pediatric
Oncology Branch, National Cancer Institute, National Institutes of
Health, Gaithersburg, MD; the Molecular and Clinical Hematology Branch,
NIDDK, and the Department of Transfusion Medicine, Clinical Center,
National Institutes of Health, Bethesda, MD; and MRC Laboratories,
University of the West Indies, Kingston, Jamaica.
Stroke is a major cause of morbidity and mortality in sickle cell
(SS) disease. Genetic risk factors have been postulated to contribute
to this clinical outcome. The human genome project has substantially
increased the catalog of variations in genes, many of which could
modify the risk for manifestations of disease outcome in a monogenic
disease, namely SS. VCAM1 is a cell adhesion molecule
postulated to play a critical role in the pathogenesis of SS disease.
We identified a total of 33 single nucleotide polymorphisms (SNPs) by
sequencing the entire coding region, 2134 bp upstream of the 5' end of
the published cDNA, 217 bp downstream of the 3' end of the cDNA, and
selected intronic regions of the VCAM1 locus. Allelic
frequencies for selected SNPs were determined in a healthy population.
We subsequently analyzed 4 nonsynonymous coding, 2 synonymous coding,
and 4 common promoter SNPs in a genetic association study of clinically
apparent stroke in SS disease conducted in a cohort derived from a
single institution in Jamaica (51 symptomatic cases and 51 matched
controls). Of the 10 candidate SNPs analyzed in this pilot study, the
variant allele of the nonsynonymous SNP, VCAM1 G1238C, may
be associated with protection from stroke (odds ratio [OR] 0.35, 95%
confidence interval [CI] 0.15-0.83, P = .04). Further
study is required to confirm the importance of this variant in
VCAM1 as a clinically useful modifier of outcome in SS disease.
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