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Received on December 2, 2004
Accepted on February 9, 2005
Molecular Diagnostics and Genetics |
ENaC Polymorphisms on the Risk of Ischemic Cerebrovascular Events: A Multicenter Case-Control Study
1 Clinical Institute for Medical and Chemical Laboratory Diagnostics
2 University Clinic of Neurology, Clinical Department of Clinical Neurology, Medical University Vienna, Vienna, Austria
3 University Clinic of Internal Medicine II, Clinical Department of Angiology, Medical University Vienna, Vienna, Austria
4 Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University Vienna, Vienna, Austria
5 Department of Human Genetics, Roche Molecular Systems, Inc., Alameda, CA
Background: Amiloride-sensitive epithelial sodium channels (ENaCs) are important candidates in the development of hypertension, which is a major risk factor for stroke. Two single-nucleotide polymorphisms (SNPs) in the gene that encodes the ENac 
-subunit (ENaC) have been identified. We evaluated those SNPs for a possible association with ischemic cerebrovascular events (ICEs).
Methods and Results: We genotyped 1399 patients with ICE [median age, 70 years; interquartile range, 58-78 years; 745 (53%) men] and 1076 control individuals without vascular disease [47 (39-58) years; 557 (52%) men] for the SNPs Trp493Arg and Ala663Thr. The SNP frequency at nucleotide 3977 (Trp493Arg) in the ENaC gene was significantly different between patients and controls. Carriers of 493Arg had a 1.78-fold increased risk (95% confidence interval, 1.02-3.12) for ICE compared with Trp/Trp carriers. Interaction analysis revealed that the relative risk was even higher in women in the lowest age tertile [adjusted odds ratio, 3.26 (1.10-9.72)].
Conclusions: Carriers of the 493Arg allele are at increased risk for ICE compared with Trp/Trp carriers. The effect is independent of traditional vascular risk factors and is particularly evident in younger women. The Trp493Arg variant in ENaC may represent an important candidate genetic susceptibility factor in the development of ICE.
The following articles in journals at HighWire Press have cited this article:
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  B. C. Rossier and L. Schild Epithelial Sodium Channel: Mendelian Versus Essential Hypertension Hypertension, October 1, 2008; 52(4): 595 - 600. [Full Text] [PDF]
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 W. Lalouschek, G. Endler, M. Schillinger, K. Hsieh, W. Lang, S. Cheng, P. Bauer, O. Wagner, and C. Mannhalter Candidate Genetic Risk Factors of Stroke: Results of a Multilocus Genotyping Assay Clin. Chem., April 1, 2007; 53(4): 600 - 605. [Abstract] [Full Text] [PDF]
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 M. S. Amin, H.-W. Wang, E. Reza, S. C. Whitman, B. S. Tuana, and F. H. H. Leenen Distribution of epithelial sodium channels and mineralocorticoid receptors in cardiovascular regulatory centers in rat brain Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1787 - R1797. [Abstract] [Full Text] [PDF]
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L. M. Silverman and T. M. Mifflin Genotype-Phenotype Correlations (II): Assessing the Influence of Sequence Variants on the Clinical Phenotype in Multifactorial Disorders Clin. Chem., June 1, 2005; 51(6): 929 - 930. [Full Text] [PDF]
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