title: Variants in genes encoding pyrophosphate metabolizing enzymes are associated with Pseudoxanthoma elasticum.
abstract: OBJECTIVE
  Pseudoxanthoma elasticum (PXE) is a rare hereditary disorder characterized by progressive calcification and fragmentation of elastic fibers. Because of the great clinical variability between PXE patients the involvement of modifier genes was recently suggested. Therefore, we investigated the association of single nucleotide variants (SNVs) in selected candidate genes known to regulate cellular pyrophosphate metabolism.
  
  
  METHODS
  We used RLFP analyses to evaluate the distribution of SNVs in alkaline phosphatase (ALP), ectonucleotide pyrophosphatase 1 (ENPP1) and ankylosis (ANKH) in DNA samples from 190 German PXE patients and 190 age- and sex-matched healthy controls. Statistical analyses were performed using Fisher exact test and Bonferroni correction.
  
  
  RESULTS
  The screening revealed three different SNVs in three genes, which were associated with PXE. The SNV c.1190-65C>A (rs1780329, minor allele frequency (MAF) patients: 0.17; controls: 0.11; P=0.04) in the ALP gene was significantly more frequent in PXE patients. Furthermore, PXE was highly associated with ANKH p.A98A genotype TT (P=0.0012), although the MAF was not different between patients and controls. After correction for multiple testing according to the Bonferroni method, one SNV in the ENPP1 gene (c.313+9G>T, rs7773477) remained significantly associated with PXE with significantly higher MAF values in the patient cohort (MAF: 0.04 vs. 0.00; P=0.0024) and a high association with PXE susceptibility (OR 27.96).
  
  
  CONCLUSIONS
  Polymorphisms in ALP, ENPP1 and ANKH are important genetic risk factors contributing to PXE.
authors.affiliation: Institut für Laboratoriums-und Transfusionsmedizin, Herz-und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany. Electronic address: mdabisch-ruthe@hdz-nrw.de.
authors.forename: Mareike
authors.initials: M
authors.lastname: Dabisch-Ruthe
authors.affiliation: Institut für Laboratoriums-und Transfusionsmedizin, Herz-und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany. Electronic address: abrock@hdz-nrw.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Brock
authors.affiliation: Institut für Laboratoriums-und Transfusionsmedizin, Herz-und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany. Electronic address: pkuzaj@hdz-nrw.de.
authors.forename: Patricia
authors.initials: P
authors.lastname: Kuzaj
authors.affiliation: Department of Ophthalmology, University of Bonn, Germany. Electronic address: peter.issa@ukb.uni-bonn.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Charbel Issa
authors.affiliation: Krankenhaus Bethesda, Dermatologie, Lehrkrankenhaus der Ruhr-Universität Bochum, Freudenberg, Germany. Electronic address: christiane.szliska@diakonie-siegen.de.
authors.forename: Christiane
authors.initials: C
authors.lastname: Szliska
authors.affiliation: Institut für Laboratoriums-und Transfusionsmedizin, Herz-und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany. Electronic address: cknabbe@hdz-nrw.de.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Knabbe
authors.affiliation: Institut für Laboratoriums-und Transfusionsmedizin, Herz-und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany. Electronic address: dhendig@hdz-nrw.de.
authors.forename: Doris
authors.initials: D
authors.lastname: Hendig
mesh_terms: D000328:Adult; D000469:Alkaline Phosphatase / Q000235:genetics*; D002114:Calcinosis / Q000235:genetics; D016022:Case-Control Studies; D004547:Elastic Tissue / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D028061:Phosphate Transport Proteins / Q000235:genetics*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011561:Pseudoxanthoma Elasticum / Q000235:genetics* / Q000473:pathology; D011755:Pyrophosphatases / Q000235:genetics*
chemical_list: C498770:ANKH protein, human; D028061:Phosphate Transport Proteins; D000469:Alkaline Phosphatase; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases
keywords: Ankylosis; Calcification; Ectonucleotide pyrophosphatase 1; Pseudoxanthoma elasticum; Tissue nonspecific alkaline phosphatase