Genetic analysis of the Irx4 gene in hypertrophic cardiomyopathy.

Objectives: The Irx4 gene is predominantly expressed in cardiac ventricles. It has been demonstrated in animal studies that disruption of the Irx4 gene causes inhibition of chamber-specific expression of myosin heavy chain genes, resulting in abnormal ventricular gene expression and cardiac hypertrophy. In this study, we aimed to investigate a possible association between mutations in the Irx4 gene and hypertrophic cardiomyopathy (HC).

Study Design: The study included 68 patients (32 females, 36 males; mean age 49 years; range 17 to 74 years) with HC and 67 healthy controls (33 females, 34 males; mean age 45 years; range 20 to 88 years). All the patients were evaluated with a detailed history, physical examination, 12-lead electrocardiography, and transthoracic echocardiography. DNA samples of all the subjects were extracted. Genomic DNA fragments were amplified by polymerase chain reaction and screened by single-strand conformation polymorphism analysis. DNA sequences were determined through an automated sequencing system.

Results: All exons in the Irx4 gene were examined. No mutations were detected associated with HC. Four polymorphisms were identified including G355>A, A381>G, G1203>A, and C1431>T. Compared with patients having the GA and GG genotyes, patients with the AA genotype of A381>G polymorphism were found to have a higher maximal left ventricle outflow tract gradient (p=0.03), prolonged corrected QT dispersion (p=0.05), and albeit not statistically significant, increased septal thickness (p=0.07).

Conclusion: This is the first human study investigating the association between the Irx4 gene and HC. Polymorphism A381>G of the Irx4 gene may have a modifier effect on septal thickness, resulting in increased corrected QT dispersion and higher outflow gradients.