Replies to post #142225 on Biotech Values

[DewDiligence]

Thanks for weighing in.

…I find it odd that the study apparently did not study the famous group of people with the Apo A-1 Milano variant…

Perhaps ApoA-1 Milano was omitted from the study because it was considered old news and hence less likely to enhance interest in the published paper.

[genisi]

However, I find it odd that the study apparently did not study the famous group of people with the Apo A-1 Milano variant who I thought clearly had a demonstrated profile with higher than normal HDL and lower than normal cardiovascular risk.

First of, a nitpick: ApoA-1 Milano carriers have lower than normal plasma HDL with low prevalence of atherosclerotic disease (so, actually, they might fit in with the data of the study if you put them in a more general way i.e.that there's no association between HDL levels and MI risk). Two reasons I can think of for not using the Milano variant, first ApoA-1 Milano is a mutation (not a polymorphism) and its gene pool is limited to a very small population mostly in Italy (all sharing a common ancestor), while the rest of us have the wild-type. So it would not be a good SNP in such epidemiological case-control association study. Second, it doesn't suit the study's hypothesis that genetically raised plasma HDL cholesterol might be protective for myocardial infarction.

[genisi]

This news upsets long held belief of mine that raising HDL, at least natural HDL (as opposed to the abnormal HDL particles associated with CETP inhibitors), is beneficial and a promising investment thesis

While these data suggest that HDL raising alone like what dalcetrapib does, has no impact on MI risk, their note here

Of note, at the cholesterol ester transfer protein (CETP) gene, we did find that common genetic variation reduces risk of myocardial infarction by 4%, a result in line with an earlier meta-analysis. However, the CETP variant both increases HDL cholesterol and lowers LDL cholesterol17 in a manner similar to pharmacological inhibitors of CETP. As such, whether the protection afforded by the CETP variant is due to the change in HDL or LDL cholesterol is difficult to distinguish.

Makes me think other CETP inhibitors that also reduce LDL might work. Of course, if we need them at all is a different question.