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Schmidt, H; Aulchenko, YS; Schweighofer, N; Schmidt, R; Frank, S; Kostner, GM; Ott, E; van Duijn, C.
Angiotensinogen promoter B-haplotype associated with cerebral small vessel disease enhances basal transcriptional activity.
STROKE. 2004; 35: 2592-2597. Doi: 10.1161/01.STR.0000144646.96121.d2 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Schmidt Helena
Co-Autor*innen der Med Uni Graz
Frank Sasa
Kostner Gerhard
Ott Erwin
Schmidt Reinhold
Schweighofer Natascha
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Abstract:
BACKGROUND AND PURPOSE: Previously, we described the presence of 5 haplotypes (A to E) at the angiotensinogen (AGT) promoter and reported a significant association between the B-haplotype (nucleotide substitutions -6:G-->A and -20:A-->C compared with the wild-type A-haplotype) and magnetic resonance imaging correlates of cerebral small vessel disease (cSVD). The association was independent of hypertension, suggesting a brain-specific effect of this haplotype. In the current study, we investigated transcriptional activities of the 5 promoter haplotypes in astrocytes, the main source of cerebral AGT, and in hepatocytes, the main source of systemic AGT, as well as determined the evolutionary relatedness of the promoter haplotypes. METHODS: Transcriptional activity depending on the haplotypes and the -6:A and -20:C substitutions was measured in transiently transfected A172 and HepG2 cells. We genotyped 5 new single nucleotide polymorphisms (SNPs) at the AGT gene and measured linkage disequilibrium (LD) among SNPs and the promoter haplotypes. An evolution-based haplotype tree was constructed. RESULTS: The B-haplotype increased transcriptional activity in both cell types. Its effect was stronger in astrocytes than in hepatocytes (2.4+/-0.09-fold, P<0.001 versus 1.6+/-0.06-fold, P=0.014). Importantly, in astrocytes the combination of the -6:A and the -20:C was mandatory for increased activity, whereas in hepatocytes the -20:C on its own was sufficient. Strong LD between the 5 new SNPs and the promoter haplotypes allowed the reconstruction of 9 haplotypes over the AGT gene. Cladistic analyses suggest that the B-haplotype represents an ancient promoter variant. CONCLUSIONS: Combination of the -6:A and -20:C substitutions in the B-haplotype may promote the development of cSVD by enhancing cerebral angiotensinogen expression.
Find related publications in this database (using NLM MeSH Indexing)
Angiotensinogen - genetics
Astrocytes - physiology
Cell Line - physiology
Cerebrovascular Disorders - genetics
Female - genetics
Haplotypes - genetics
Hepatocytes - physiology
Humans - physiology
Linkage Disequilibrium - physiology
Male - physiology
Middle Aged - physiology
Mutation - physiology
Polymorphism, Single Nucleotide - physiology
Promoter Regions (Genetics) - physiology
Transcription, Genetic - physiology
Transfection - physiology

Find related publications in this database (Keywords)
angiotensinogen
gene expression regulation
genetics
white matter
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