on October 7, 2004
Published online before print October 7, 2004, doi: 10.1161/01.STR.0000144646.96121.d2
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Submitted on May 6, 2004
From the Institute of Medical Molecular Biology and Biochemistry (H.S., N.S., S.F., G.M.K.), and the Department of Neurology (R.S., E.O.), Medical University of Graz, Austria; and the Genetic Epidemiology Unit (Y.S.A., C.v.D.), Erasmus University, Rotterdam, the Netherlands. * To whom correspondence should be addressed. E-mail: helena.schmidt{at}uni-graz.at.
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 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.
Revised on June 17, 2004
Accepted on July 5, 2004
Angiotensinogen Promoter B-Haplotype Associated With Cerebral Small Vessel Disease Enhances Basal Transcriptional Activity
Helena Schmidt MD, MSc*;
A and -20:AC 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.
Key words: angiotensinogen • gene expression regulation • genetics • white matter
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