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Re: DewDiligence post# 142136

Friday, 05/18/2012 5:11:25 PM

Friday, May 18, 2012 5:11:25 PM

Post# of 252248
HDL may not be so Good afterall

This news has been getting a lot of press this week. In addition to the Globe article referenced, the NYTimes ran a prominent article yesterday.

The news is actually based on an article published so far in online issue of Lancet. The summary is pasted below for reference. But, the article is quite technical and hard to understand for someone not versed in modern genetic terminology. My own take is that the correlation between HDL and cardiovascular risk is more complicated than we thought and HDL could even be a marker for something else that is more directly causative.

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.

I suspect the next step will be to tease out effects of the various subtypes of HDL, some of which I predict will be shown to be cardioprotective and some may even be associated with increased risk.

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. My long floundering investment in Resverlogix warrants further scrutiny.

Urche

The Lancet, Early Online Publication, 17 May 2012
Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
Summary
Background
High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
Methods
We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.
Findings
Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10-13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84—0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88—1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58—0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68—1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45—1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69—2·69, p=2×10-10).
Interpretation
Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.

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