AMPD1 gene mutations are associated with obesity and diabetes in Polish patients with cardiovascular diseases

Abstract

Previous studies showed an association of the common functional polymorphism (C34T, Gln12Stop) in the adenosine monophosphate deaminase-1 (AMPD1) gene with survival in heart failure (HF) and/or coronary artery disease (CAD). The aim of the study was to search for other mutations in selected regions of the AMPD1 gene in Polish CAD and HF patients, and to analyze their associations with obesity and diabetes. Exons 2, 3, 5, and 7 of AMPD1 were scanned for mutations in 97 patients with CAD without HF (CAD+ HF−), 104 patients with HF (HF+), and 200 newborns from North-Western Poland using denaturing high-performance liquid chromatography (DHPLC), polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), and direct sequencing. Frequencies of AMPD1 C34T mutation, as well as novel A99G, G512A, IVS4-6delT, and C784T sequence alterations, were similar in the three groups, but 860T mutated allele was less frequent in the combined CAD+ HF− and HF+ groups than in the controls (1.7% vs. 4.3%, p = 0.040). Heterozygous 34CT genotype was associated with lower (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.13–0.81) and 860AT with higher (OR = 13.7, 95%CI = 1.6–118) prevalence of diabetes or hyperglycemia in relation to wild-type homozygotes. Abdominal obesity was more frequent in 860AT patients than in wild-type homozygotes and 34CT heterozygotes (86% vs. 40% vs. 29%, p < 0.05). Nine genes containing polymorphisms linked with AMPD1 C34T mutation were found in the HapMap database. AMPD1 C34T nonsense mutation is associated with reduced prevalence of diabetes and obesity in patients with CAD or HF, but A860T substitution seems to exert opposite metabolic effects and should always be accounted for in the studies of the AMPD1 genotype.

Activity of AMP-Regulated Protein Kinase and AMP-Deaminase in the Heart of Mice Fed High-Fat Diet

“…Most common is point mutation C34T (Glu12Stop) in exon 2. [10] C34T mutation decreases activity of AMPD1 in the heart of patients heterozygous for this mutation. [11] The research on patients with dilated cardiomyopathy demonstrated better survival without transplantation in patients carrying C34T mutation as well as better function in heart donors.…”

“…[12] Some studies demonstrated lower incidence of diabetes in patients with C34T mutation. [10] Therefore, the associations of altered AMPD activity with cardiovascular pathology in diabetes needs to be studied further.…”

Inhibition of AMP deaminase as therapeutic target in cardiovascular pathology

“…In controls 860T mutated allele was more frequent than in the combined CAD+ HFÀ and HF+ groups. Nonsense mutation in AMPD 1 (C34T) was associated with reduced prevalence of diabetes and obesity in patients with CAD or HF [52], but this investigation reveals that A860T substitution seems to exert opposite metabolic effects [53].…”

JAZF1 promotes proliferation of C2C12 cells, but retards their myogenic differentiation through transcriptional repression of MEF2C and MRF4—Implications for the role of Jazf1 variants in oncogenesis and type 2 diabetes

“…In this context, the Ampd1 gene was selected for subsequent analyses because it was sensitive to both JAZF1 overexpression and downregulation, which conversely downregulated and upregulated Ampd1 expression, respectively (Supplementary Table 2). Furthermore, Ampd1 mutations are known to be associated with obesity and diabetes [23,24].…”