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Cardiovascular Consequences of Cholesterol Drugs Modeled Using Target Gene Variants

NEW YORK (GenomeWeb) – The cardiovascular benefits of lowering low-density lipoprotein cholesterol (LDL-C) may be more complex than initially appreciated, according to findings from a new genetic association study published in the Journal of the American Medical Association.

Members of an international research team led by investigators at Wayne State University and Harvard Medical School considered genotyping data for hundreds of thousands of individuals from prior cohort or case-control studies, focusing on variants in the cholesteryl ester transfer protein (CETP) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) genes. Their goal was to identify a cardiovascular risk, if any existed, associated with variants that affect the same genes targeted by CETP inhibitors and statins, respectively.

Past research has pointed to ties between high LDL-C levels, lower-than-usual high-density lipoprotein cholesterol (HDL-C), and cardiovascular disease, the team explained. Even so, in a recent Phase 3 randomized clinical trial of a CETP inhibitor drug that dialed down LDL-C levels and boosted levels of the presumably beneficial HDL-C, heart disease risk did not show a corresponding decline, prompting questions about the effectiveness of this approach.

"Because the cardiovascular outcome trials have evaluated the effect of treatment with a CETP inhibitor on the background of statin therapy, the associations of the CETP variants were evaluated both alone and in combination with variants of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene, which encodes the target of statins," corresponding author Brain Ference, a cardiovascular medicine researcher at Wayne State University, and his co-authors wrote.

The team initially considered genotyping data for 102,837 individuals from 14 studies, including individuals who had experienced 13,821 major cardiovascular events. In that group, individuals carrying more CETP variants tended to have enhanced levels of HDL-C, diminished LDL-C levels overall, and lower-than-usual levels of the LDL-C component apolipoprotein B (apoB).

The presence of CETP variants also appeared somewhat protective in this discovery group, the researchers reported — findings they verified by analyzing data for 189,539 individuals enrolled in the four-dozen more past studies, representing 62,200 coronary heart disease cases.

But a somewhat different pattern emerged when the team looked at CETP and HMGCR variants in combination. Although individuals with variants in both genes still tended to have lower LDL-C and higher HDL-C levels, their levels of the risky apoB particles did not dip quite as much. And that slight increase in apoB appeared to be enough to affect the risk of cardiovascular event, the results suggested. 

"Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels," they explained, noting that cardiovascular event risk dipped alongside that apoB reduction, while LDL-C changes alone seemed to have less pronounced effects on the risk of cardiovascular events.

Based on these results, Ference and his co-authors concluded that the "clinical benefit of lowering LDL-C levels may … depend on the corresponding reduction in apoB-containing lipoprotein particles."

In an editorial appearing in the same issue of JAMA, McGill University researchers Allan Sniderman and Eric Peterson, with Duke University, cautioned that the genetic variants in question might not produce effects that are directly comparable to the effects of drugs that target these genes. Still, they said, the results do seem to fit patterns being observed in the clinic and may offer clues to the complex relationships between lipids and cardiovascular risk.

'These genetic studies were consistent not only with the results of the CETP inhibitor trials but also with several prior epidemiological discordance analyses, which demonstrated that when the LDL-C level is high but the apoB level is low, cardiovascular risk is low," the duo wrote. "By contrast, when the LDL-C level is low but the apoB level is high, cardiovascular risk is high."

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