Osteopontin gene variation and cardio/cerebrovascular disease phenotypes

Abstract

a b s t r a c tWe aimed at associating common osteopontin (OPN) gene variants with cardiovascular disease phenotypes.We scanned the OPN gene in 190 chromosomes from myocardial infarction (MI) patients and identified five variants in the promoter, three synonymous and one non-synonymous variant. All variants were investigated in case-control studies for MI (ECTIM: 990 cases, 900 controls) and brain infarction (BI) (GÉNIC: 466 cases, 444 controls). Promoter variants were functionally analyzed by bandshift assays, the coding D147D [T/C] by Western blot. Allele D147D C was independently and significantly associated with lower apoB levels (P = 0.044 [ECTIM] P = 0.03 [GENIC]), its allele frequency was significantly lower in patients with BI compared to controls (OR [95% CI] 0.39 [0.20-0.74], P = 0.004), and C allele carriers had a significantly lower frequency of presence of carotid plaques (P = 0.02). Bandshifts with HepG2 and Ea.hy926 nuclear proteins did not reveal any functionality of promoter variants, whereas the OPN-441C-containing construct resulted in reduced OPN protein expression in Western blots, complying with its potential protective effect on the phenotypes studied.We here provide evidence that a portion of the OPN locus is likely to associate with cardiovascular disease-related phenotypes. However, further experiments are warranted to clarify the functional role of OPN variants.

The rs1126616 Single Nucleotide Polymorphism of the Osteopontin Gene Is Independently Associated with Cardiovascular Events in a Chronic Kidney Disease Cohort

“…The results of the present study demonstrate that rs1126616 polymorphism of the SPP1 gene is independently associated with a higher incidence of CVE in a cohort of CKD patients. A previous study from Brand-Herrmann and colleagues did not find any association of the SPP1 rs1126616 SNP to myocardial or brain infarction [19], but differs from our study in many aspects. The NEFRONA study is a prospective cohort study of mainly CKD patients, and our endpoint (CVE) is a composite containing all cardiovascular events.…”

“…Again, the fact that their cohort was not composed of CKD patients, and that they only focus on AAA could explain differences between both studies. It is worth noting that none of these studies [19,45] tested different genetic models of inheritance, precluding the identification of the over dominant genotype that arose in our study. Usually genetic disease models follow dominant, recessive, or co-dominant models, but over dominant models have been also described in many studies [46,47,48,49].…”

“…Apart from plasma OPN levels, single nucleotide polymorphisms (SNPs) on the SPP1 gene (the gene encoding OPN), have also been associated with atheromatous disease and cardiovascular events [19]. For instance, rs28357094 located at the SPP1 promoter has been shown to be related with increased carotid intima media thickness (cIMT) [20,21].…”

The Role of Osteopontin (OPN/SPP1) Haplotypes in the Susceptibility to Crohn's Disease

“…The selection of these SNPs was based on previous studies in which associations for several of these OPN variants with autoimmune and Th1- and Th17-mediated diseases have been shown [40], [41], [42], [43], [49], [50], [51], [52], [53]. The donor fluorescent molecule (fluorescein) at the 3′-end of the sensor probe (or the anchor probe in the case of rs2853744 and rs11730582) is excited at its specific fluorescence excitation wavelength (533 nm) and the energy is transferred to the acceptor fluorescent molecule at the 5′-end (LightCycler Red 610, 640 or 670) of the anchor probe (or the sensor probe in the case of rs2853744 and rs11730582).…”

“…We also investigated for potential epistasis with IBD-associated IL23R gene variants. In total, we genotyped nine common single nucleotide polymorphisms (SNPs) in the OPN gene, which were previously shown to be associated with other immune-mediated diseases [40], [41], [42], [43]. Last, based on the important role demonstrated for IL-22 in colitis experiments in Opn−/− mice [39], we analyzed the effect of OPN gene variants on IL-22 serum levels.…”