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Variants in the VCAM1 gene and risk for symptomatic stroke in sickle cell disease
James G Taylor1, Delia C Tang, Sharon A Savage
1Section on Genomic Variation, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Gaithersburg, MD 20877, USA.
Insights
Genetic variations in the VCAM1 gene may influence stroke risk in sickle cell disease patients. A specific VCAM1 SNP (G1238C) showed potential protective effects against stroke in a pilot study.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Stroke is a significant complication in sickle cell (SS) disease, impacting morbidity and mortality.
- Genetic factors are suspected to influence the risk of developing stroke in SS disease patients.
- VCAM1, a cell adhesion molecule, is implicated in the pathogenesis of SS disease.
Purpose of the Study:
- To investigate single nucleotide polymorphisms (SNPs) in the VCAM1 gene as potential genetic risk factors for stroke in sickle cell disease.
- To identify specific VCAM1 variants that may modify stroke risk in SS disease.
Main Methods:
- Sequencing of the VCAM1 locus, including coding, upstream, downstream, and intronic regions, to identify SNPs.
- Determination of allelic frequencies for selected SNPs in a healthy population.
- Genetic association study analyzing 10 candidate VCAM1 SNPs in a cohort of SS disease patients with and without stroke.
Main Results:
- A total of 33 SNPs were identified in the VCAM1 locus.
- The variant allele of the nonsynonymous SNP, VCAM1 G1238C, was associated with a reduced risk of stroke (OR 0.35, 95% CI 0.15-0.83, P =.04).
- This finding suggests a potential protective role of this VCAM1 variant against stroke in SS disease.
Conclusions:
- The VCAM1 G1238C SNP may be a protective genetic factor against stroke in sickle cell disease.
- Further research is needed to validate the role of this VCAM1 variant as a clinical modifier of stroke risk in SS disease.
- Identifying genetic modifiers could lead to improved stroke risk prediction and prevention strategies in SS disease.
Abstract:
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.