Ecto-5' -Nucleotidase CD73 (NT5E), vitamin D receptor and FGF23 gene polymorphisms may play a role in the development of calcific uremic arteriolopathy in dialysis patients - Data from the German Calciphylaxis Registry

PLoS One. 2017 Feb 17;12(2):e0172407. doi: 10.1371/journal.pone.0172407. eCollection 2017.

Abstract

Introduction: Calciphylaxis/calcific uremic arteriolopathy affects mainly end-stage kidney disease patients but is also associated with malignant disorders such as myeloma, melanoma and breast cancer. Genetic risk factors of calciphylaxis have never been studied before.

Methods: We investigated 10 target genes using a tagging SNP approach: the genes encoding CD73/ ecto-5'-nucleotidase (purinergic pathway), Matrix Gla protein, Fetuin A, Bone Gla protein, VKORC1 (all related to intrinsic calcification inhibition), calcium-sensing receptor, FGF23, Klotho, vitamin D receptor, stanniocalcin 1 (all related to CKD-MBD). 144 dialysis patients from the German calciphylaxis registry were compared with 370 dialysis patients without history of CUA. Genotyping was performed using iPLEX Gold MassARRAY(Sequenom, San Diego, USA), KASP genotyping chemistry (LGC, Teddington, Middlesex, UK) or sequencing. Statistical analysis comprised logistic regression analysis with adjustment for age and sex.

Results: 165 SNPs were finally analyzed and 6 SNPs were associated with higher probability for calciphylaxis (OR>1) in our cohort. Nine SNPs of three genes (CD73, FGF23 and Vitamin D receptor) reached nominal significance (p< 0.05), but did not reach statistical significance after correction for multiple testing. Of the CD73 gene, rs4431401 (OR = 1.71, 95%CI 1.08-2.17, p = 0.023) and rs9444348 (OR = 1.48, 95% CI 1.11-1.97, p = 0.008) were associated with a higher probability for CUA. Of the FGF23 and VDR genes, rs7310492, rs11063118, rs13312747 and rs17882106 were associated with a higher probability for CUA.

Conclusion: Polymorphisms in the genes encoding CD73, vitamin D receptor and FGF23 may play a role in calciphylaxis development. Although our study is the largest genetic study on calciphylaxis, it is limited by the low sample sizes. It therefore requires replication in other cohorts if available.

MeSH terms

  • 5'-Nucleotidase / genetics*
  • Aged
  • Aged, 80 and over
  • Calciphylaxis / etiology
  • Calciphylaxis / genetics*
  • Case-Control Studies
  • Female
  • Fibroblast Growth Factors / genetics*
  • GPI-Linked Proteins / genetics
  • Genetic Predisposition to Disease
  • Germany
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Receptors, Calcitriol / genetics*
  • Registries
  • Renal Dialysis / adverse effects
  • Uremia / etiology
  • Uremia / genetics*

Substances

  • GPI-Linked Proteins
  • Receptors, Calcitriol
  • VDR protein, human
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • 5'-Nucleotidase
  • NT5E protein, human

Grant support

This work was supported by AMGEN, grant name: CASPAC. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.