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Clinical Chemistry 0: clinchem.2006.083675v1, 2007; 10.1373/clinchem.2006.083675
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Received on November 24, 2006
Accepted on February 20, 2007

Molecular Diagnostics and Genetics

SPP1 Promoter Polymorphisms: Identification of the First Modifier Gene for Pseudoxanthoma Elasticum

Doris Hendig 1, Marius Arndt 1, Christiane Szliska 2, Knut Kleesiek 1, Christian Götting 1*

1 Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, Germany
2 Dermetologische Klinik, Krankenhaus Bethesda, 57258 Freudenberg, Germany

* To whom correspondence should be addressed. E-mail: cgoetting{at}hdz-nrw.de.

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 ~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 (Pcorrected < 0.05 each). The odds ratios (95% confidence interval) 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 (Pcorrected = 0.035, odds ratio 1.80, 95% confidence interval 1.19-2.71).

Conclusions: Polymorphisms in the SPP1 promoter are secondary genetic risk factors contributing to PXE susceptibility.


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R. Zarbock, D. Hendig, C. Szliska, K. Kleesiek, and C. Gotting
Vascular endothelial growth factor gene polymorphisms as prognostic markers for ocular manifestations in pseudoxanthoma elasticum
Hum. Mol. Genet., September 1, 2009; 18(17): 3344 - 3351.
[Abstract] [Full Text] [PDF]


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