This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison
LDLR Microarrays
GEO, or Gene Expression Omnibus, was used in order to search for DNA microarray experiments that dealt with LDLR expression or FH. A search for LDLR within gene profiles found many studies that measured LDLR expression in humans and other species. A dataset search also found three studies in which FH patients were compared to normal subjects in order to compare gene expression. The results can be found below.
Figure 1-LDLR expression in control cells compared to cells treated with 1,2,4-benzenetriol. Click to access website.
The first experiment tests the effect of benzene on gene expression levels using 1,2,4-benzenetriol, a benzene derivative that mimics the carcinogenicity of its cousin. Using cultured peripheral blood mononuclear cells, the researchers compared the levels of gene expression in cells treated with 1,2,4-benzenetriol to untreated cells. The above figure is the quantification of LDLR expression: it can be seen that the treated cells have about a 25% increase in LDLR expression.
However, DNA microarrays can detect differences in expression of thousands of genes simultaneously. This allows researchers to view gene expression patterns across the genomes of different cell types and under different conditions. DNA microarrays will hopefully be a powerful clinical tool in the future. In this first experiment, the cluster map (found here) gives a visualization of the expression of all 22215 genes in the 16 individuals within the study. This particular map does not seem to have an obvious pattern associated with 1,2,4-benzenetriol treatment. However, the cluster map does not match up with the LDLR map shown in figure 1. I expected the order of individuals in the LDLR graph to correspond with the individuals in the cluster map, thus the first eight individuals were untreated and the last eight were treated with 1,2,4-benzenetriol. Surprisingly, the cluster map has untreated and treated individuals mixed together, making any sort of comparison impossible. I really don't understand why this discrepancy would exist in a microarray analysis; comparing two samples is the purpose of the assay.
However, DNA microarrays can detect differences in expression of thousands of genes simultaneously. This allows researchers to view gene expression patterns across the genomes of different cell types and under different conditions. DNA microarrays will hopefully be a powerful clinical tool in the future. In this first experiment, the cluster map (found here) gives a visualization of the expression of all 22215 genes in the 16 individuals within the study. This particular map does not seem to have an obvious pattern associated with 1,2,4-benzenetriol treatment. However, the cluster map does not match up with the LDLR map shown in figure 1. I expected the order of individuals in the LDLR graph to correspond with the individuals in the cluster map, thus the first eight individuals were untreated and the last eight were treated with 1,2,4-benzenetriol. Surprisingly, the cluster map has untreated and treated individuals mixed together, making any sort of comparison impossible. I really don't understand why this discrepancy would exist in a microarray analysis; comparing two samples is the purpose of the assay.
Figure 2-LDLR expression in normal individuals compared to individuals with Marfan syndrome. Click to access website.
The above figure shows another study comparing normal individuals to those suffering from a connective tissue disorder, Marfan syndrome. Like the first experiment, LDLR expression is slightly larger in those with the disease compared to the normal individuals. As with the first experiment, the LDLR graph individuals do not match up with the individuals in the cluster map (found here). Interestingly, this cluster map does seem to have an expression pattern. This pattern is most noticable within the last third off the genes; the first half of individuals are most downregulated (green) and the other half of individuals are mostly upregulated (magenta). It is not apparent if this pattern is a result of the cluster map organization or if it is because of gene expression differences in those suffering from Marfan syndrome compared to normal individuals.
I also searched GEO for studies involving individuals with FH. Three FH studies were found and all dealt with atherosclerosis research. Each study used microarrays to detect gene expression differences in people with FH compared to normal individuals. The entire datasets could be downloaded, however due to the size (>45Mb), I decided not to. Only one study has published their findings in which they used monocyte cells from normal and FH individuals for the comparison. The researchers found that 1,617 genes were upregulated and 701 genes were downregulated in FH individuals (1). I would have really like to view a cluster map of this study, in order to gain a better understanding of the genome-wide differences in individuals with FH. I am especially interested in the regulation of other cholesterol metabolism genes in FH. See the Future Directions page for more information on this subject.
References
1. Mosig, S., Rennert, K. Buttner, P., Krause, S., Lutjohann, D., Soufl, M., Heller, R., Funke, H. (2008). Monocytes of patients with familial hypercholesterolemia show alterations in cholesterol metabolism. BMC Medical Genomics, 1, 60. doi:10.1186/1755-8794-1-60
