The role of HDL in atherosclerosis

Prof. M. John Chapman (Paris, France)in discussion with

Dr. Kees Hovingh (Amsterdam, The Netherlands)

Genetics (1)

What is the relationship between functional mutations in the major genes

involved in HDL metabolism and cardiovascular risk?

Genetics of HDL metabolism (1)

• Studying families with carries of mutations

• Mutations in LCAT, ABCA1, ApoA-1

HDL metabolism

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

ApoA-1

Genetics (2)

Should we widen our studies of the key genes within a specific family or cohort?

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

Systems biology

Is this approach comparable with systems biology?

Systems biology (1)

• Measure enzymatic endpoints

• Concept: impact of a gene on the phenotype

• We might have been using the wrong system

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

HDL-mediated cholesterol efflux from cholesterol-rich macrophages

• apo E

• apo A-1

Rader DJ. J Clin Invest. 2006;116:3090–3100.

Systems biology (3)

• Effort to define standard culture conditions

• Complexity of the HDL or ApoA-1 ligand

Mechanisms of cellular cholesterol efflux to HDL particles

HDL metabolism: impact of CETP inhibition

Systems biology (4)

• CETP: most significant gene (genome studies)

• Reevaluate our ex vivo/in vitro approaches

Controversy

Is the controversy mainly associated with the systems that have been used?

Controversy

Great deal of difference between the expression of these receptors, not only in macrophages from different species, but also in human conditions