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 resistanceassociated 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 ϳ2-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

Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population

“…The G base insertion at À156 site of OPN promoter generates another Runx2-binding site, 19,22 and Runx2 bindings are crucial for regulation of OPN transcription in bone tissue. 36 As discussed above, enhanced expression of OPN in heart potentially causes cardiac dysfunction.…”

“…17,18 Recently, three functional polymorphisms (À66T/G, À156del/G and À443T/C) on the promoter region of OPN gene have been found to affect gene expression by altering transcriptional activity 19 and reported to be associated with several diseases, including pseudoxanthoma elasticum, stroke and chronic hepatitis C. [20][21][22] The insertion of guanine base at position À156 (À156G allele) on the OPN promoter generates a Runx2 binding site so that the binding of Runx2 factor to the À156G position promotes OPN transcription. 19 In the present study, we investigated the association between diastolic dysfunction and the À156del/G polymorphism on the OPN promoter in patients with hypertension.…”

Pseudoxanthoma elasticum: Wide phenotypic variation in homozygotes and no signs in heterozygotes for the c.3775delT mutation in ABCC6

“…In another study, promoter polymorphisms of the SPP1 gene were significantly more often present in patients with PXE than in controls, so that it was suggested that SPP1 is a modifier gene for PXE. 29 Furthermore, a correlation was reported between polymorphisms in three genes encoding for antioxidant enzymes (CAT, SOD2, and GPX1) and age of onset of PXE. 30 Higher serum concentrations of the calcification inhibitor matrix Gla protein (MGP) were correlated with later onset of PXE.…”

SPP1 promoter polymorphisms and glioma risk in a Chinese Han population

“…The allele and genotype frequencies differed from those previously reported in Caucasians. 20 The allele frequencies of the À443C/T SNP for SPP1T were 0.654 in controls and 0.672 in patients. The genotype frequencies of this site for CC, CT and TT in cases and controls were 0.103, 0.448, 0.448 and 0.115, 0.463, 0.423, respectively ( Table 2).…”