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The role of HDL in atherosclerosis
Prof. M. John Chapman (Paris, France)in discussion with
Dr. Kees Hovingh (Amsterdam, The Netherlands)
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Genetics (1)
What is the relationship between functional mutations in the major genes
involved in HDL metabolism and cardiovascular risk?
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Genetics of HDL metabolism (1)
• Studying families with carries of mutations
• Mutations in LCAT, ABCA1, ApoA-1
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HDL metabolism
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Genetics of HDL metabolism (2)
• Relatively small number of subjects
• Heterozygous carriers: increased IMT
• Lack of large numbers and relevance of the genes
• Different groups showing different data
• ApoA-1, one of the best targets of atherosclerosis
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ApoA-1
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Genetics (2)
Should we widen our studies of the key genes within a specific family or cohort?
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Genetics of HDL metabolism (2)
• Individual with SRB1 mutation, but a low-normal HDL level: counterintuitive
• Sequencing ApoA-1, LCAT and ABCA1• Neutralizing effects of other monogenetic
disorders: HDL level and CAD risk• Sequencing a lot of genes all at once• Better view of the landscape of genetic disorders
underpinning HDL levels
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Systems biology
Is this approach comparable with systems biology?
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Systems biology (1)
• Measure enzymatic endpoints
• Concept: impact of a gene on the phenotype
• We might have been using the wrong system
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Systems biology (2)
• Our field: primarily focused on murine cell lines
• Also human cell lines: little relation to the profile in in vitro cultured macrophages
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HDL-mediated cholesterol efflux from cholesterol-rich macrophages
• apo E
• apo A-1
Rader DJ. J Clin Invest. 2006;116:3090–3100.
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Systems biology (3)
• Effort to define standard culture conditions
• Complexity of the HDL or ApoA-1 ligand
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Mechanisms of cellular cholesterol efflux to HDL particles
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HDL metabolism: impact of CETP inhibition
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Systems biology (4)
• CETP: most significant gene (genome studies)
• Reevaluate our ex vivo/in vitro approaches
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Controversy
Is the controversy mainly associated with the systems that have been used?
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Controversy
Great deal of difference between the expression of these receptors, not only in macrophages from different species, but also in human conditions