Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner


Individuals born with a genetic predisposition toward high plasma high-density lipoprotein (HDL) cholesterol levels do not have a lower risk of myocardial infarction, calling into question whether HDL cholesterol is causally related to cardiovascular risk, researchers found.

In a mendelian randomization analysis, individuals carrying a single nucleotide polymorphism (SNP) associated exclusively with higher plasma HDL cholesterol had higher levels of the lipid, but a myocardial infarction (MI) risk similar to that of other individuals (OR 0.99, 95% CI 0.88 to 1.11, P=0.85), according to Sekar Kathiresan, MD, of Massachusetts General Hospital in Boston, and colleagues.

On the other hand, a collection of SNPs related to higher low-density lipoprotein (LDL) cholesterol levels was associated with an increased risk of MI, as expected (OR 2.13, 95% CI 1.69 to 2.69), the researchers reported online in The Lancet.

“These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction,” they wrote.

In addition, “these findings emphasize the potential limitation of plasma HDL cholesterol as a surrogate measure for risk of myocardial infarction in intervention trials.”

Observational studies have shown a relationship between higher HDL cholesterol levels and a lower risk of MI, but it remains unclear whether the relationship is causal. Agents aimed at increasing HDL cholesterol levels have not been shown to reduce cardiovascular risk in randomized trials.

Kathiresan and colleagues first evaluated the effect of a SNP in the endothelial lipase gene (LIPG Asn396Ser), which is related to higher HDL cholesterol levels. About 2.6% of individuals carry the allele.

Among four prospective cohort studies, carriers of the allele had HDL cholesterol levels that were higher, on average, by 0.14 mmol/L (5.4 mg/dL).

That difference would be expected to decrease the risk of MI by a relative 13% (OR 0.87, 95% CI 0.84 to 0.91), if the relationship between HDL cholesterol and MI risk were causal. But the allele was not associated with risk of MI among six prospective cohort studies and 14 case-control studies that included 20,913 patients with MI and 95,407 controls.

A genetic score consisting of 14 SNPs exclusively associated with HDL cholesterol was not associated with MI risk either (OR 0.93, 95% CI 0.68 to 1.26).

The authors acknowledged the inherent limitations to mendelian randomization, including the absence of an association of individual SNPs with MI because of low statistical power.

In an accompanying editorial, Steve Humphries, PhD, of University College London, and colleagues noted that the study is consistent with previous mendelian randomization analyses focused on the same issue and adds to an increasing number of mendelian randomization studies of coronary heart disease biomarkers.

“As the research area matures, a consensus for methodology and reporting will be important, particularly when the potentially powerful, but also complex, genetic risk score approach is used,” they wrote. “Taken together with adequately powered studies, mendelian randomization is likely to yield insights that can both guide public health policy and prioritize potential therapeutic targets.”

The study was funded by the NIH, the Wellcome Trust, European Union, British Heart Foundation, and German Federal Ministry of Education and Research. The collection of clinical and sociodemographic data in the Dortmund Health Study was supported by the German Migraine Headache Society (DMKG) and by unrestricted grants of equal share from AstraZeneca, Berlin Chemie, Boots Healthcare, GlaxoSmithKline, McNeil Pharma (formerly Woelm Pharma), MSD Sharp Dohme, and Pfizer to the University of Muenster.

Kathiresan serves on a scientific advisory board for Merck and has received research grants from Pfizer, Shire Therapeutics, and Alnylam Pharmaceuticals. Four of the authors are employees of or own stock options in deCODE Genetics, or both. Four other authors are full-time employees of GlaxoSmithKline. The rest of the authors reported relationships with Merck, Servier, AstraZeneca, Pfizer, Novartis, and Boehringer Ingelheim.

Humphries is medical director and minority shareholder of the University College London start-up coronary heart disease risk genetic testing company Storegene, and has received honoraria for speaking at educational meetings with a pharmaceutical sponsor, donating all sums to medical charities.

Primary source: The Lancet
Source reference:
Voight B, et al “Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomization study” Lancet 2012; DOI: 10.1016/S0140-6736(12)60312-2.

Additional source: The Lancet
Source reference:
Harrison S, et al “Mendelian randomization, lipids, and cardiovascular disease” Lancet 2012; DOI: 10.1016/S0140-6736(12)60481-4.


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