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Clinical Chemistry 53: 829-836, 2007. First published March 23, 2007; 10.1373/clinchem.2006.083675
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(Clinical Chemistry. 2007;53:829-836.)
© 2007 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

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

Doris Hendig1, Marius Arndt1, Christiane Szliska2, Knut Kleesiek1 and Christian Götting1,a

1 Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, Germany.
2 Dermatologische Klinik, Krankenhaus Bethesda, 57258 Freudenberg, Germany.
3 Human genes: ABCC6, ATP-binding cassette subfamily C, member 6; CFTR, cystic fibrosis transmembrane conductance regulator (ATP-binding cassette subfamily C, member 7); SPP1, secreted phosphoprotein 1 (previously OPN, osteopontin); and XYLT1, XYLT2: xylosyltransferase I and II.

aAddress correspondence to this author at: Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Georgstraße 11, 32545 Bad Oeynhausen, Germany. Fax +49-5731-97-2013; 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% 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 (Pcorrected = 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.






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