Role of adenosine monophosphate deaminase-1 gene polymorphism in patients with congestive heart failure (influence on tumor necrosis factor-α level and outcome)

• Published in: The American journal of cardiology Vol. 93; no. 10; pp. 1260 - 1264
• Main Authors: Gastmann, Anja, Sigusch, Holger H, Henke, Andreas, Reinhardt, Dirk, Surber, Ralf, Gastmann, Oliver, Figulla, Hans R
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15.05.2004; Elsevier; Elsevier Limited
• Subjects: AMP Deaminase - genetics; Biological and medical sciences; Cardiology. Vascular system; DNA Primers; Enzyme-Linked Immunosorbent Assay; Enzymes; Female; Genes; Germany; Heart; Heart failure; Heart Failure - blood; Heart Failure - genetics; Heart Failure - mortality; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Humans; Male; Medical sciences; Middle Aged; Polymerase Chain Reaction; Polymorphism; Polymorphism, Genetic; Survival Analysis; Tumor Necrosis Factor-alpha - metabolism; Tumors; Tumors of the heart; Germany; Human; Heart failure; Prognosis; Enzyme; Cytokine; Cardiovascular disease; Adenosine deaminase; Phlebology; Heart tumor; Gene; Heart disease; Hydrolases; Evolution; Level; Circulatory system; Cardiology; Influence factor; Tumor necrosis factor α; Polymorphism
• ISSN: 0002-9149; 1879-1913
• DOI: 10.1016/j.amjcard.2004.02.011

The Cytosin→thymidin transition at codon 12 of the adenosine monophosphate deaminase-1 (AMPD1) gene results in a complete loss of its catalytic activity. The increased conversion of adenosine monophosphate to adenosine, which in turn attenuates the expression of tumor necrosis factor-α (TNF-α) expression, has been suggested as a putative mechanism for prolonged survival in patients with congestive heart failure (CHF) carrying the mutant AMPD1 allele. Therefore, the impact of this polymorphism on circulatory TNF-α concentrations and outcome in patients with CHF should be studied. The AMPD1 genotype of each patient with CHF (n = 90; idiopathic dilated cardiomyopathy n = 53; coronary artery disease n = 20; other n = 17) was determined by direct sequencing. Serum TNF-α concentrations were measured by enzyme-linked immunosorbent assay. We found 66 patients (75.6%) to be homozygous for the wild-type allele (AMPD1 +/+), and 20 patients (22.2%) were heterozygous and 2 were homozygous (2.2%) for the mutant AMPD1 allele (AMPD1 ± or −/−). TNF-α serum concentrations were 4.2 ± 2.0 pg/ml for the AMPD1 +/+ genotype and 5.3 ± 2.9 pg/ml for the AMPD1 ± and −/− genotypes (p = 0.045). A downregulation of TNF-α in patients carrying the mutant allele could therefore be not detected. However, Kaplan-Meier analysis demonstrated a significantly prolonged survival without heart transplantation or revival from sudden death in the AMPD1 ± & −/− group (p = 0.020). Multivariate analysis identified the AMPD1 wild-type genotype as an independent risk factor (odds ratio 9.34, 95% confidence interval 1.78 to 48.96). The mutant AMPD1 allele, in the context of CHF, is associated with a prognostic benefit. The underlying mechanism of TNF-α is unrelated.