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Clinical Chemistry 51: 952-956, 2005. First published February 25, 2005; 10.1373/clinchem.2004.046276
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(Clinical Chemistry. 2005;51:952-956.)
© 2005 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Impact of {alpha}ENaC Polymorphisms on the Risk of Ischemic Cerebrovascular Events: A Multicenter Case–Control Study

Kety Hsieh1, Wolfgang Lalouschek2, Martin Schillinger3, Georg Endler1, Manuela Reisinger1, Michael Janisiw1, Wilfried Lang2, Suzanne Cheng4, Oswald Wagner1,a and Christine Mannhalter1,a

1 Clinical Institute for Medical and Chemical Laboratory Diagnostics, 2 University Clinic of Neurology, Clinical Department of Clinical Neurology, and 3 University Clinic of Internal Medicine II, Clinical Department of Angiology, Medical University Vienna, Vienna, Austria.
4 Department of Human Genetics, Roche Molecular Systems, Inc., Alameda, CA.

aThese authors shared responsibility for the project and should both be considered corresponding authors. Address for correspondence: Clinical Institute of Medical and Chemical Laboratory Diagnostics, AKH-Wien, Waehringer Guertel 18-20, 1097 Vienna, Austria. Fax 43-1-40400-2097; e-mail christine.mannhalter{at}meduniwien.ac.at or oswald.wagner{at}meduniwien.ac.at.

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 {alpha}-subunit ({alpha}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 ICEs [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 frequencies at nucleotide 3977 (Trp493Arg) in the {alpha}ENaC gene were significantly different in patients and controls. Carriers of 493Arg had a 1.78-fold increased risk (95% confidence interval, 1.02–3.12) for ICEs 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 ICEs 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 {alpha}ENaC may represent an important candidate genetic susceptibility factor in the development of ICEs.




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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
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Distribution of epithelial sodium channels and mineralocorticoid receptors in cardiovascular regulatory centers in rat brain
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L. M. Silverman and T. M. Mifflin
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