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Cardiovasc Res. 2011 Aug 1;91(3):465-71. doi: 10.1093/cvr/cvr083. Epub 2011 Mar 22.

A gain-of-function SNP in TRPC4 cation channel protects against myocardial infarction.

Author information

1
Laboratory of Molecular Physiology and Channelopathies, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, C/ Dr. Aiguader 88, Barcelona, Spain.

Abstract

AIMS:

The TRPC4 non-selective cation channel is widely expressed in the endothelium, where it generates Ca(2+) signals that participate in the endothelium-mediated vasodilatory response. This study sought to identify single-nucleotide polymorphisms (SNPs) in the TRPC4 gene that are associated with myocardial infarction (MI).

METHODS AND RESULTS:

Our candidate-gene association studies identified a missense SNP (TRPC4-I957V) associated with a reduced risk of MI in diabetic patients [odds ratio (OR) = 0.61; confidence interval (CI), 0.40-0.95, P= 0.02]. TRPC4 was also associated with MI in the Wellcome Trust Case-Control Consortium's genome-wide data: an intronic SNP (rs7319926) within the same linkage disequilibrium block as TRPC4-I957V showed an OR of 0.86 (CI, 0.81-0.94; P =10(-4)). Functional studies of the missense SNP were carried out in HEK293 and CHO cells expressing wild-type or mutant channels. Patch-clamp studies and measurement of intracellular [Ca(2+)] in response to muscarinic agonists and direct G-protein activation showed increased channel activity in TRPC4-I957V-transfected cells compared with TRPC4-WT. Site-directed mutagenesis and molecular modelling of TRPC4-I957V suggested that the gain of function was due to the presence of a less bulky Val-957. This permits a firmer interaction between the TRPC4 and the catalytic site of the tyrosine kinase that phosphorylates TRPC4 at Tyr-959 and facilitates channel insertion into the plasma membrane.

CONCLUSION:

We provide evidence for the association of a TRPC4 SNP with MI in population-based genetic studies. The higher Ca(2+) signals generated by TRPC4-I957V may ultimately facilitate the generation of endothelium- and nitric oxide-dependent vasorelaxation, thereby explaining its protective effect at the vasculature.

PMID:
21427121
DOI:
10.1093/cvr/cvr083
[Indexed for MEDLINE]

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