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

Carole Jung , Gemma G. Gené , Marta Tomás , Cristina Plata , Jana Selent , Manuel Pastor , César Fandos , Mariano Senti , Gavin Lucas , Roberto Elosua , Miguel A. Valverde
DOI: http://dx.doi.org/10.1093/cvr/cvr083 465-471 First published online: 22 March 2011

Abstract

Aims The TRPC4 non-selective cation channel is widely expressed in the endothelium, where it generates Ca2+ 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 [Ca2+] 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 Ca2+ 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.

  • Myocardial infarction
  • TRP ion channels
  • Calcium
  • Genetics of cardiovascular diseases
  • Gene polymorphisms
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