title: 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.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Klinikum Coburg, Coburg, Germany.|Department of Medicine, Division of Nephrology, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Hansjörg
authors.identifier: http://orcid.org/0000-0003-1163-6576
authors.initials: H
authors.lastname: Rothe
authors.affiliation: Department of Cardiology, RWTH University of Aachen, Aachen, Germany.
authors.forename: Vincent
authors.initials: V
authors.lastname: Brandenburg
authors.affiliation: Division for Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Margot
authors.initials: M
authors.lastname: Haun
authors.affiliation: Division for Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kollerits
authors.affiliation: Division for Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Kronenberg
authors.affiliation: Klinikum Coburg, Coburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Ketteler
authors.affiliation: Department of Medicine, Division of Nephrology, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D002115:Calciphylaxis / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics*; D058851:GPI-Linked Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000235:genetics*; D012042:Registries; D006435:Renal Dialysis / Q000009:adverse effects; D014511:Uremia / Q000209:etiology / Q000235:genetics*
chemical_list: C000717427:FGF23 protein, human; D058851:GPI-Linked Proteins; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D015720:5'-Nucleotidase; C548241:NT5E protein, human