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

Autor: Gavin Lucas, Cristina Plata, Mariano Sentí, Manuel Pastor, Marta Tomás, Jana Selent, Carole Jung, Miguel A. Valverde, Gemma G. Gené, Roberto Elosua, César Fandos
Rok vydání: 2011
Předmět:
Male
Models
Molecular
Linkage disequilibrium
Patch-Clamp Techniques
Protein Conformation
Physiology
Myocardial Infarction
Bioinformatics
TRPC4
Linkage Disequilibrium
Membrane Potentials
Gene Frequency
Risk Factors
Cricetinae
Odds Ratio
Phosphorylation
education.field_of_study
Exons
Middle Aged
Phenotype
medicine.anatomical_structure
Intronic SNP
Female
Cardiology and Cardiovascular Medicine
Adult
medicine.medical_specialty
Genotype
Endothelium
Population
Single-nucleotide polymorphism
CHO Cells
Muscarinic Agonists
Biology
Transfection
Polymorphism
Single Nucleotide
Risk Assessment
Diabetes Complications
Structure-Activity Relationship
Cricetulus
Physiology (medical)
Internal medicine
medicine
Animals
Humans
SNP
Calcium Signaling
education
Genetic Association Studies
Aged
TRPC Cation Channels
Genetic association
Analysis of Variance
Chi-Square Distribution
HEK293 Cells
Logistic Models
Endocrinology
Spain
Case-Control Studies
Mutagenesis
Site-Directed
Zdroj: Cardiovascular Research. 91:465-471
ISSN: 1755-3245
0008-6363
Popis: 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.
Databáze: OpenAIRE
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