title: A gain-of-function SNP in TRPC4 cation channel protects against myocardial infarction.
abstract: OBJECTIVE
  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).
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, C/ Dr. Aiguader 88, Barcelona, Spain.
authors.forename: Carole
authors.initials: C
authors.lastname: Jung
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Gené
authors.forename: Marta
authors.initials: M
authors.lastname: Tomás
authors.forename: Cristina
authors.initials: C
authors.lastname: Plata
authors.forename: Jana
authors.initials: J
authors.lastname: Selent
authors.forename: Manuel
authors.initials: M
authors.lastname: Pastor
authors.forename: César
authors.initials: C
authors.lastname: Fandos
authors.forename: Mariano
authors.initials: M
authors.lastname: Senti
authors.forename: Gavin
authors.initials: G
authors.lastname: Lucas
authors.forename: Roberto
authors.initials: R
authors.lastname: Elosua
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Valverde
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D016466:CHO Cells; D020013:Calcium Signaling; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D006224:Cricetinae; D003412:Cricetulus; D048909:Diabetes Complications / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D008958:Models, Molecular; D018721:Muscarinic Agonists / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D016017:Odds Ratio; D018408:Patch-Clamp Techniques; D010641:Phenotype; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D018570:Risk Assessment; D012307:Risk Factors; D013030:Spain; D013329:Structure-Activity Relationship; D050052:TRPC Cation Channels / Q000737:chemistry / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D018721:Muscarinic Agonists; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel