Together with Clint Miller and Tom Quertermous from Stanford University and others we have worked on the TCF21 locus which has recently identified to be genome-wide significantly associated with coronary artery disease.
The results of this collaborative work have been published online at PlosGenetics just yesterday.
PlosGenetics
In 2010, Tom and his team in Stanford and our group in Lübeck started independently to work on the genetic mechanism at the TCF21 locus. Over the years we learned from each other and in the end we decided to put our data together to tell a really interesting and convincing story on how an intronic SNP dysregulates TCF21 by disrupting a miRNA binding site.
Here is what our Authors Summary tells about the paper:
Both genetic and environmental factors cumulatively contribute to coronary heart disease risk in human populations. Large-scale meta-analyses of genome-wide association studies have now leveraged common genetic variation to identify multiple sites of disease susceptibility; however, the causal mechanisms for these associations largely remain elusive. One of these disease-associated variants, rs12190287, resides in the 3′untranslated region of the vascular developmental transcription factor, TCF21. Intriguingly, this variant is shown to disrupt the seed binding sequence for microRNA-224, and through altered RNA secondary structure and binding kinetics, leads to dysregulated TCF21 gene expression in response to disease-relevant stimuli. Importantly TCF21 and miR-224 expression levels were perturbed in human atherosclerotic lesions. Along with our previous reports on the transcriptional regulatory mechanisms altered by this variant, these studies shed new light on the complex heritable mechanisms of coronary heart disease risk that are amenable to therapeutic intervention.
JE
The results of this collaborative work have been published online at PlosGenetics just yesterday.
PlosGenetics
In 2010, Tom and his team in Stanford and our group in Lübeck started independently to work on the genetic mechanism at the TCF21 locus. Over the years we learned from each other and in the end we decided to put our data together to tell a really interesting and convincing story on how an intronic SNP dysregulates TCF21 by disrupting a miRNA binding site.
Here is what our Authors Summary tells about the paper:
Both genetic and environmental factors cumulatively contribute to coronary heart disease risk in human populations. Large-scale meta-analyses of genome-wide association studies have now leveraged common genetic variation to identify multiple sites of disease susceptibility; however, the causal mechanisms for these associations largely remain elusive. One of these disease-associated variants, rs12190287, resides in the 3′untranslated region of the vascular developmental transcription factor, TCF21. Intriguingly, this variant is shown to disrupt the seed binding sequence for microRNA-224, and through altered RNA secondary structure and binding kinetics, leads to dysregulated TCF21 gene expression in response to disease-relevant stimuli. Importantly TCF21 and miR-224 expression levels were perturbed in human atherosclerotic lesions. Along with our previous reports on the transcriptional regulatory mechanisms altered by this variant, these studies shed new light on the complex heritable mechanisms of coronary heart disease risk that are amenable to therapeutic intervention.
JE
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