SPP1 promoter polymorphisms: identification of the first modifier gene for pseudoxanthoma elasticum
| Autor: | Knut Kleesiek, Doris Hendig, Marius Arndt, Christian Götting, Christiane Szliska |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Adult
Male Adolescent Haploview Clinical Biochemistry Molecular Sequence Data ABCC6 Risk Factors Genotype medicine Humans Genetic variability Allele Pseudoxanthoma Elasticum Promoter Regions Genetic Chromatography High Pressure Liquid Aged Genetics Polymorphism Genetic biology Base Sequence Biochemistry (medical) Haplotype Promoter Sequence Analysis DNA Middle Aged Pseudoxanthoma elasticum medicine.disease Haplotypes Case-Control Studies biology.protein Female Osteopontin |
| Zdroj: | Clinical chemistry. 53(5) |
| ISSN: | 0009-9147 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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