Polymorphism in exon 6 of the human NT5E gene is associated with aortic valve calcification

Abstract

NT5E encodes ecto-5'-nucleotidase (e5NT, CD73) which hydrolyses extracellular AMP to adenosine. Adenosine has been shown to play a protective role against aortic valve calcification (AVC). We identified two nonsynonymous missense single nucleotide polymorphisms (c.1126A > G, p.T376A and c.1136T > C, p.M379T) in exon 6 of the human NT5E gene. Since both substitutions might affect e5NT activity and consequently alter extracellular adenosine levels, we evaluated the association between NT5E alleles and calcific aortic valve disease in 119 patients (95 patients with AVC and 24 controls). In AVC patients, the frequency of the G allele at c.1126 and the frequency of the GG genotype as well as the frequency of the C allele at c.1136, and the frequencies of CC and TC genotypes tended to be higher as compared to controls. The allele and genotype frequencies in AVC patients and controls were also compared to those calculated from the 1000 Genomes Project data for control individuals of European ancestry (n = 503). We found that the frequency of the C allele at c.1136 is significantly higher in patients with AVC than in the European controls (0.111 vs. 0.054, P = 0.0052). Moreover, e5NT activity in aortic valves showed a trend toward lower levels in AVC patients with CC and TC genotypes than in those with the TT genotype. Our findings indicate that the genetic polymorphism of NT5E may contribute to the pathogenesis of calcific aortic valve disease and that the C allele of SNP c.1136 is associated with an increased risk of AVC.

The new insight into extracellular NAD+ degradation‐the contribution of CD38 and CD73 in calcific aortic valve disease

“…Reduced CD73 expression may be associated with the presence of inflammation and contribute to the development of aortic valve dysfunction 16 . This is also consistent with publications where mutations in the NT5E gene, which encodes CD73, lead to altered extracellular nucleotide metabolism and progression in ectopic tissue calcification in the CAVD patient cohort 20,21 . In contrast to these results, it has been reported that stenotic aortic valves can exhibit overexpression of CD73 29 …”

“…Other deletion effects in mice include dyslipidaemia and intracellular lipid accumulation in muscle, 17 impairment of tubuloglomerular feedback regulation of GFR, 18 and altered thromboregulation and augmented vascular inflammatory responses 19 . Moreover, mutations in the NT5E gene, which encodes CD73, lead to disturbances of extracellular nucleotide metabolism and progression in ectopic tissue calcification in humans 20,21 …”

Rare Co-occurrence of Beta-Thalassemia and Pseudoxanthoma elasticum: Novel Biomolecular Findings

“…As far as rs699664 in GGCX, rs4236 in MGP, and rs2229523 in NT5E genes, data in the literature (30)(31)(32) indicate that SNPs observed in our patients determine either an enzyme activity similar to wildtype (GGCX Arg325Gln and NT5E Thr376Ala ) or absent association with increased risk of calcification (MGP Thr102Ala ) and therefore their functional contribution to the ectopic mineralization phenotype can be likely irrelevant.…”

Association of the ENPP1/ENTPD1 Polymorphisms in Hemodialysis Patients

“…The ATP-ADP-AMP-adenosine axis (Figure 1) 1 is an important energy metabolism pathway identified in vivo. The enzymes involved in the axis, including NT5E/CD73 (5ʹ-nucleotidase, ecto), ENPP1 (Ectonucleotide pyrophosphatase/phosphodiesterase 1), and ENTPD1/CD39 (Ectonucleoside triphosphate diphosphohydrolase 1) appear to have an association with severe ectopic calcification, [2][3][4] which was a common complication on hemodialysis (HD) patients and also tightly connected with cardiovascular disease (CVD).…”