Genetic Study Questions HDL Levels and the Risk of MI

FYI-High or Low HDL levels do NOT affect a lower or higher risk of having a heart attack- The entire HDL supposition that a high HDL level protects people from having a heart attack is once again shown to be an incorrect medical belief that has no truth. Jerry

[www.medscape.com]
Genetic Study Questions HDL Levels and the Risk of MI
Michael O'Riordan
Authors and Disclosures


May 17, 2012 (Boston, Massachusetts) — Therapies that boost HDL-cholesterol levels are currently viewed as a potential treatment to close down the residual risk of aggressively treated patients, but data from a new study throw cold water on the putative benefits of raising HDL-cholesterol levels to reduce the risk of MI [1].
Investigators report that a genetic variant that substantially raises HDL-cholesterol levels did not alter the risk of MI, whereas genetic polymorphisms related to plasma LDL-cholesterol were consistently associated with an increased risk of MI.
"These results challenge several established views about plasma HDL cholesterol," write Dr Benjamin Voight (University of Pennsylvania, Philadelphia) and colleagues in a report published online May 16, 2012 in the Lancet. "First, these data question the concept that raising plasma HDL cholesterol should uniformly translate into reduction in risk of myocardial infarction. . . . Second, these findings emphasize the potential limitation of plasma HDL cholesterol as a surrogate measure for risk of myocardial infarction in intervention trials."

In an editorial accompanying the study [2], Drs Seamus Harrison, Michael Holmes, and Steve Humphries (University College London, UK) echo the conclusions of the researchers, stating that "genetically raised HDL-cholesterol concentrations do not seem to reduce risk of coronary heart disease--an observation that calls into question whether raising HDL cholesterol therapeutically would translate into the expected clinical benefit."

The genetic data emerge after a couple of high-profile failures with drugs, as well as extended-release niacin, which showed no benefit in terms of hard clinical events despite substantial increases in HDL-cholesterol levels.

Earlier this month, Roche stopped the phase 3 dal-OUTCOMES trial of the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib after interim analysis of the study showed the HDL-cholesterol–boosting drug did not reduce cardiovascular adverse events.

The AIM-HIGH study, with niacin given on top of statin therapy, showed the vitamin significantly increased HDL-cholesterol levels but failed to reduce the composite end point of coronary heart disease death, nonfatal MI, ischemic stroke, or hospitalization for acute coronary syndrome or symptom-driven coronary or cerebral revascularization. And of course, torcetrapib, another CETP inhibitor, was stopped in late 2006 when investigators discovered the drug increased the risk of death and cardiovascular events.

HDL and MI: It's a Complicated Relationship
In the present study, the researchers performed two Mendelian analyses. With the first, they tested the association with a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn 396Ser) in 95 407 healthy controls and 20 913 patients who had an MI.

Carriers of the LIPG Asn 396Ser allele, which occurred in 2.6% of the study cohort, had HDL-cholesterol levels approximately 5.5 mg/dL (0.14 mmol/L) higher than those without the allele but similar levels of other lipids. Despite the increase in HDL cholesterol, carriers of the LIPG Asn 396Ser allele did not have a significantly decreased risk of MI (odds ratio 0.99; 95% CI 0.88–1.11). Similarly, in an analysis of six prospective cohort studies alone, which included 46 535 controls and 4228 MI patients, as well as a separate analysis of case-control studies, there was no significant association between the LIPG Asn 396Ser allele and the risk of MI.
On the basis of the association between the LIPG Asn 396Ser allele and HDL cholesterol, the increase in HDL should have translated into a 13% decreased risk of MI.

The researchers also constructed a genetic score by combining common SNPs that had statistical evidence at genomewide levels of significance for plasma LDL- and HDL-cholesterol levels. The genetic score for LDL and HDL cholesterol included 13 and 14 SNPs, respectively. In the Mendelian randomized analysis, each standard-deviation (SD) increase in LDL cholesterol due to the genetic score significantly increased the risk of MI (OR 2.13; 95% CI 1.69–2.69). In contrast, each 1-SD increase in HDL cholesterol due to the genetic score did not decrease the risk of MI.

Based on these data, "interventions (lifestyle or pharmacological) that raise plasma HDL cholesterol cannot be assumed ipso facto to lead to a corresponding benefit with respect to risk of myocardial infarction," conclude Voight and colleagues.

Trials with drugs that raise HDL cholesterol remain ongoing. More data on the use of niacin will come from the 24 000-patient HPS2-THRIVE study, while other CETP inhibitors, evacetrapib (Lilly, Indianapolis, Indiana) and anacetrapib (Merck, Whitehouse Station, NJ), are still in development.