SPP1 promoter polymorphisms: identification of the first modifier gene for pseudoxanthoma elasticum.
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.
Hendig
Doris
D
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, Germany.
Arndt
Marius
M
Szliska
Christiane
C
Kleesiek
Knut
K
Götting
Christian
C
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
C506895:SPP1 protein, human; D053495:Osteopontin