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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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