medwireNews: Researchers have constructed a polygenic risk score (PRS) comprising endothelial cell (EC)-specific gene variants that may help identify individuals who are vulnerable to the atherogenic effects of low-density lipoprotein cholesterol (LDL-C) and are therefore good candidates for aggressive lipid-lowering.
Nicholas Marston (Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA) and colleagues examined genome-wide significant single nucleotide polymorphisms associated with coronary artery disease (CAD), 35 of which had a demonstrated role in EC function. These were included in the EC PRS and its association with the risk for incident CAD was then tested in three cohorts.
The first was 348,967 individuals (57.6% women, mean age 56.4 years) from the UK Biobank who were not on statins at baseline and had a median LDL-C level of 142 mg/dL. The patients were stratified as having a low (bottom 20%), intermediate (middle 60%), or high (top 20%) EC PRS.
Individuals with a high EC PRS were found to have a 44% greater risk for CAD than those with low or intermediate scores, after taking into account traditional risk factors such as high blood pressure.
The EC PRS also significantly predicted the development of CAD over a median follow-up of 12 years, with each standard deviation (SD) significantly increasing the risk by 24%, a risk prediction that “is on a par with established modifiable risk factors,” such as increased systolic blood pressure, glycated hemoglobin, and high sensitivity C-reactive protein, note the researchers.
The magnitude of effect was also comparable to that of an LDL PRS based on 46 loci that affected CAD and LDL-C, which increased the risk for CAD by 27% with each 1 SD. The team reports that the two PRS were weakly correlated and had an additive effect, with individuals with both a high LDL and EC PRS nearly fourfold more likely to develop CAD than those with low LDL and EC PRS.
LDL-C concentration significantly modified the association between the EC PRS and CAD risk, say Marston et al. For example, in individuals with a natural LDL-C concentration of 150 mg/dL, each SD of EC PRS increased the risk for CAD by 26%, whereas the EC PRS was no longer associated with CAD risk in individuals with a LDL-C level of 50 mg/dL.
Furthermore, the team found that individuals with a high EC PRS benefited the most from lipid-lowering therapy after analyzing data on individuals from the second two cohorts. These were 8749 individuals (67.8% men, mean age 66.1 years) from the JUPITER trial of statin therapy (rosuvastatin) as primary CAD prevention, and 14,298 participants (76.3% men, mean age 62.9 years) of the FOURIER trial assessing the addition of a PCSK9 inhibitor (evolocumab) to statin therapy as secondary prevention. The participants’ median baseline LDL-C levels were a respective 110 mg/dL and 92 mg/dL.
Rosuvastatin reduced the risk for CAD over a median follow-up of 1.9 years by a significant 72% among those with a high EC PRS compared with only a 29% risk reduction for those with intermediate or low scores. Similarly, evolocumab reduced the risk for CAD over a median follow-up of 2.2 years by a significant 33% in individuals with a high EC PRS, compared with only an 8% reduction in those with intermediate or low scores.
However, the EC PRS was no longer associated with CAD risk in patients who achieved a median LDL-C of 54 mg/dL with rosuvastatin therapy or 28 mg/dL with evolocumab therapy.
“If [LDL-C] levels are kept below 60 or 70 mg/dL, there may not be enough lipoproteins to traverse the arterial endothelium and enter the vessel wall,” say the study authors.
Although a causal role of EC dysfunction in the development of atherosclerosis is unclear, Marston et al say that their findings suggest “EC PRS not only defines a unique pathway of CAD risk but also identifies LDL-C sensitive individuals with an actionable genotype in whom targeted intervention can provide greater benefit.”
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