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

• Published in: Cardiovascular research 2011-08, Vol.91 (3), p.465-471
• Main Authors: Jung, Carole, Gené, Gemma G., Tomás, Marta, Plata, Cristina, Selent, Jana, Pastor, Manuel, Fandos, César, Senti, Mariano, Lucas, Gavin, Elosua, Roberto, Valverde, Miguel A.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Analysis of Variance; Animals; Biological and medical sciences; Calcium Signaling; Cardiology. Vascular system; Case-Control Studies; Chi-Square Distribution; CHO Cells; Coronary heart disease; Cricetinae; Cricetulus; Diabetes Complications - genetics; Diabetes Complications - metabolism; Diabetes Complications - prevention & control; Exons; Female; Gene Frequency; Genetic Association Studies; Genotype; Heart; HEK293 Cells; Humans; Linkage Disequilibrium; Logistic Models; Male; Medical sciences; Membrane Potentials; Middle Aged; Models, Molecular; Muscarinic Agonists - pharmacology; Mutagenesis, Site-Directed; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - prevention & control; Myocarditis. Cardiomyopathies; Odds Ratio; Patch-Clamp Techniques; Phenotype; Phosphorylation; Polymorphism, Single Nucleotide; Protein Conformation; Risk Assessment; Risk Factors; Spain; Structure-Activity Relationship; Transfection; TRPC Cation Channels - chemistry; TRPC Cation Channels - drug effects; TRPC Cation Channels - genetics; TRPC Cation Channels - metabolism
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvr083

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.