Bio 362 Human Genetics Spring 2008
Atherosclerosis study sheet for February 5th
Back to syllabus

Lusis, 2000:
Make an outline or flow chart (as mentioned in the syllabus) of the events that lead to atherosclerosis, including examples of important gene products that contribute at each step. My own flow chart includes about ten steps. Don't get bogged down in all the details--try to flesh out what is important.

Oram, 2002
What is reverse cholesterol transport?
What happens to ApoA in people with Tangier disease?
Fig 1: What are the two models for how ABCA1 works? Which fits best with existing experimental evidence?
In what cell types in the body does ABCA1 function?
The text says that ABCA1 activity in macrophages is of minor importance to HDL levels-- what sort of experiment do you think was done to show this?
What's known about ABCA1 in biliary excretion? (What are bile salts?)
What is the function of ABCA1 in reverse transport? What experiments with knockout mice and transgenic mice overexpressing ABC1A were done to explore this? How is the experimental evidence conflicting?
How is the ABC1A gene activated? (What is a nuclear receptor?)
Is ABCA1 a good candidate for gene therapy for atherosclerosis? Are there other possible treatment approaches?

Pajukanta, 2004
What's the relationship between single-gene and complex forms of the same disease?
What's a SNP?
What are the three questions asked in the research paper that is described in this commentary?
Whose DNA was examined initially? How?
What was found? Then whose DNA was examined, and for what? How were common and rare variants treated differently in the experimental analysis?
What conclusions were made about the role of rare ABC1A variants in cholesterol levels in the population?
What were the conclusions about the role of common variants in cholesterol levels in the population?
What might have been missed?
Are there any implications for treatments?

Joyce et al., 2002
We will take an abbreviated look at this paper, focusing on the first half mainly (Table 1 and Figures 1 and 2), but you should figure out in a general sense what the second half of the paper demonstrates.
Which apolipoproteins (ApoA, ApoB, ApoE) are involved with the ABCA1 transporter and which ones are associated with LDL and HDL?
What was the goal of this study?
There were two main comparisons in this study. What mouse genotypes were studied in each case? Why?
In the first comparison, what were the effects of the transgene on lipid profiles (Table 1)?
What were the effects of the transgene on lipoprotein levels (Figure 1)? Be able to annotate this figure in detail. Note that CD stands for Regular Chow Diet and HFHC stands for High Fat High Cholesterol Diet.
How did the transgene affect atherosclerosis in the aorta?
In a general sense, what was the overall conclusion in the second half of the paper, and what was surprising? What are the crucial aspects of Figures 3 and 4? What might be the explanation for the unexpected results?

Timmins et al., 2005 (questions from Molly and Laura)
1. What is the function of ABCAI in the regulation of HDL assembly?  What is the function of HDL?
2. Describe the process that floxed alleles are made and how it determined the exons had been excised?
3.  How was it proven that the removal of the exons made the ABCAI gene ineffective?
4.  Compare figures five and six.
5.  What is the significance of lipid-efflux?
6. How are atherosclerosis and Tangier's related in the context of this article?
7.  What is the gene dosage effect and why is it important?
8.  Discuss catabolism rates in the liver and kidney