title: SPP1 promoter polymorphisms: identification of the first modifier gene for pseudoxanthoma elasticum.
abstract: BACKGROUND
  Progressive calcification and fragmentation of elastic fibers are characteristic hallmarks of pseudoxanthoma elasticum (PXE), which is caused by mutations in ABCC6 encoding multidrug resistance-associated protein 6 (MRP6). Because of the great clinical variability of PXE, secondary genetic risk factors are suspected to exist. We investigated whether SPP1 (secreted phosphoprotein 1; previously OPN, osteopontin) promoter polymorphisms are associated with PXE.
  
  
  METHODS
  We screened an approximately 2-kb region spanning the theoretical promoter of the SPP1 gene for sequence variations by denaturing HPLC and direct sequencing in 93 PXE patients. Sequence variations with a prevalence >5% were genotyped in 93 age- and sex-matched healthy controls. Statistical and haplotype association analyses were performed using Fisher exact test, PHASE v2.1.1, and Haploview 3.2.
  
  
  RESULTS
  Mutational screening revealed 9 different sequence variations. Three SPP1 promoter polymorphisms (c.-1748A>G, c.-155_156insG, and c.244_245insTG) were significantly more frequent in PXE patients than in 93 age- and sex-matched healthy controls (P(corrected) < 0.05 each). The odds ratios (95% CI) for PXE among carriers of the 3 alleles were, respectively, 2.16 (1.34-3.48), 2.41 (1.51-3.82), and 1.97 (1.23-3.15). Haplotype analysis of 6 SPP1 promoter polymorphisms revealed 1 haplotype to be significantly reduced among PXE patients (P(corrected) = 0.035, odds ratio 1.80, 95% CI 1.19-2.71).
  
  
  CONCLUSIONS
  Polymorphisms in the SPP1 promoter are secondary genetic risk factors contributing to PXE susceptibility.
authors: Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, Germany.
authors: Doris
authors: D
authors: Hendig
authors: Marius
authors: M
authors: Arndt
authors: Christiane
authors: C
authors: Szliska
authors: Knut
authors: K
authors: Kleesiek
authors: Christian
authors: C
authors: Götting
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D053495:Osteopontin / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011561:Pseudoxanthoma Elasticum / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA
chemical_list: C506895:SPP1 protein, human; D053495:Osteopontin