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HDL Cholesterol Boost Alone Does Not Reduce Cardiovascular Disease Risk, Genetic Study Suggests

NEW YORK (GenomeWeb) – The ability to boost high-density lipoprotein (HDL) levels alone does not seem to dial down cardiovascular disease risk, according to a new genetic study done in China.

To investigate this possibility, researchers from the UK, China, and the US used insurance records, disease registry data, and death reports to compare cardiovascular disease prevalence — and lipid levels, when possible — in more than 150,000 East Asian biobank participants genotyped at a handful of variants in the CETP gene, which codes for a cholesteryl ester transfer protein. Generally speaking, variants or pharmacologic agents that diminish CETP gene product activity are thought to enhance HDL levels.

As the team reported online today in JAMA Cardiology, results from the association study suggest that the presence of the CETP variants considered did lead to higher-than-usual HDL cholesterol in the blood. But those variants did not coincide with a drop in potentially risky low-density lipoprotein cholesterol levels, the group noted. It did not see ties between these variants and non-vascular conditions except eye disease, which was more common in those with the rare, loss-of-function CETP variant.

"CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for [cardiovascular disease]," corresponding author Iona Millwood, an epidemiologist and population health researcher at the University of Oxford, and her co-authors wrote. "These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for [cardiovascular disease]."

Declining HDL cholesterol levels have been linked to cardiovascular disease, coronary heart disease, and/or stroke risk in past epidemiological studies, the team noted, hinting that there might be preventative benefits to boosting HDL cholesterol concentrations. Even so, there is debate over the consequences of lowering CETP activity with targeted drugs, prompting exploration of lipid levels and cardiovascular effects in individuals carrying genetic variants in the CETP genes.

In a JAMA study published in August, for example, researchers from Wayne State University, Harvard Medical School, and elsewhere saw an association between CETP variation, increased HDL cholesterol, and decreased LDL cholesterol levels, with slight protection against coronary heart disease. But patterns were more complicated in individuals from that study who carried additional variants in enzyme-coding genes related to those targeted by statin drugs.

For the latest analysis of genetic factors influencing cholesterol levels, investigators used Illumina or Affymetrix arrays to genotype 151,217 individuals between the ages of 30 and 79, from five urban and five rural sites in China.

With samples collected at baseline, they had access to blood lipid measurements for 17,854 individuals and lipoprotein measurements in more than 4,600 individuals. Tapping into health insurance records, disease registry, and death certificate data also offered them a look at the incidence of cardiovascular and other disease in this group over a median follow up time of just a little more than nine years.

The team's analyses focused on five CETP variants associated with CETP activity and/or HDL cholesterol levels in the past — including four common variants and one rarer loss-of-function mutation previously described in the East Asian population.

Both the common and the loss-of-function variants were associated with an uptick in HDL cholesterol overall, for example, along with higher large and medium HDL particle levels, lower blood levels of very low-density lipoprotein particles, and lower systolic blood pressure.

The researchers did not see significant associations between rare CETP variant status or the broader CETP genetic score with vascular conditions such as major vascular disease, myocardial infarction, intracerebral hemorrhage, or stroke. Similarly, they did not turn up clear ties to other conditions such as diabetes or cancer, though the rare variant did coincide with a slight rise in eye disease risk.

All told, the study's authors concluded that their results offer "no evidence to support a beneficial association with [cardiovascular disease] of increasing HDL cholesterol concentration through CETP inhibition."

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