Role of adenosine monophosphate deaminase-1 gene polymorphism in patients with congestive heart failure (influence on tumor necrosis factor-alpha level and outcome).
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-alpha (TNF-alpha) 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-alpha 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-alpha 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-alpha 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-alpha 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-alpha is unrelated.
Gastmann
Anja
A
Department of Internal Medicine, Division of Cardiology and Institute of Virology, University of Jena, Erlanger Allee 101, D-07740 Jena, Germany.
Sigusch
Holger H
HH
Henke
Andreas
A
Reinhardt
Dirk
D
Surber
Ralf
R
Gastmann
Oliver
O
Figulla
Hans R
HR
D000659:AMP Deaminase / Q000235:genetics*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005858:Germany; D006333:Heart Failure / Q000097:blood / Q000235:genetics* / Q000401:mortality*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D017931:DNA Primers; D014409:Tumor Necrosis Factor-alpha; D000659:AMP Deaminase