Gene Test Could Predict Subclinical CHD Risk, Statin Benefit

Marlene Busko

March 06, 2017

BOSTON, MA — A risk score for coronary heart disease (CHD) based on a blood test to detect 57 single nucleotide polymorphisms (SNPs) may identify patients with subclinical atherosclerosis and those who would derive greater benefit from statin therapy for primary prevention, researchers report[1].

The three-part study by Dr Pradeep Natarajan (Harvard Medical School, Boston, MA) and colleagues was published online February 21, 2017 in Circulation.

First, among men with hypercholesterolemia in the West of Scotland Coronary Prevention Study (WOSCOPS) trial who received statins for primary prevention of CHD, the risk of a CHD event was reduced by 44% in patients with a high genetic risk score but only by 24% in other patients—even though the LDL-cholesterol lowering was the same in both groups.

The results were similar in a meta-analysis of WOSCOPS and two other primary-prevention trials.

Last, in two other observational trials, patients with a high genetic risk score had greater coronary artery calcification and a higher carotid plaque burden.

"Conventional teaching suggests that all [patient] subgroups benefit equally with respect to coronary heart disease reduction for a given amount of LDL-cholesterol lowering," Natarajan told heartwire from Medscape. "This study provides evidence for potentially the first subgroup that responds differently for a given amount of LDL-cholesterol lowering."

"What this [study] provides evidence for is a genetic blood test that identifies people with such elevated risk who can potentially benefit more from statin therapy. I think the next step is to actually test this in a prospective, randomized clinical trial. "

Previous Studies, New WOSCOPS Study, and Meta-Analysis

Previously, using a risk score based on 27 SNPs in a cohort from several primary- and secondary-prevention trials, Natarajan and colleagues reported that patients in the top risk quintile had a greater risk reduction in CHD from statin therapy than other patients.

Similarly, two other primary prevention trials—the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA) trial of atorvastatin vs placebo in patients with hypertension, and the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial of rosuvastatin vs placebo in patients with high C-reactive protein—reported that patients at high genetic risk had a greater benefit from statin therapy, despite similar LDL-cholesterol lowering.

The researchers aimed to test a risk score based on 57 SNPs, in another cohort: 4910 men in WOSCOPS who had hypercholesterolemia and were 45 to 64 years old when they were randomized to receive pravastatin or placebo to prevent CHD (nonfatal MI or death from CHD). The patients were followed for 4.8 years in the trial and 8.8 years beyond that.

LDL cholesterol was lowered by the same amount in patients with a high genetic risk score (in the top quintile) and in other patients (about 44 mg/dL [22.9%] in each group).

The risk of a first CHD event was reduced by 44% in patients who had a high genetic risk score (HR 0.56, 95% CI 0.40–0.78; P<0.001) but only by 24% in the other patients (HR 0.76, 95% CI 0.63–0.92; P=0.004).

The absolute risk reduction for a CHD event was 7.9% among patients with a high genetic risk score vs 2.7% among all other patients. Thus, the number needed to treat (NNT) with a statin to prevent one coronary event was 13 among patients with a high genetic risk score and 38 among all other patients.

Similarly, in a meta-analysis of patients from WOSCOPS plus 6978 patients from ASCOTT-LLA and 8769 patients from JUPITER, the risk for a first CHD event was reduced by 46% in patients with a high genetic risk score and by 26% in other patients.

In the meta-analysis, the absolute risk reduction for a CHD event was 3.6% among patients at high genetic risk vs 1.3% among others, so the NNT with a statin to prevent one coronary event was 28 among high-genetic-risk participants and 80 among all others.

Genetic Risk and Subclinical Atherosclerosis

To examine how genetic risk for CHD was linked with subclinical atherosclerosis, the researchers analyzed data from participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study who were 32 to 47 years old when coronary artery calcium was determined, as well as participants from the BioImage Study who were 55 to 80 years old when carotid plaque burden was determined.

In CARDIA, for every standard-deviation increase in the genetic risk score, the odds ratio for the presence of coronary artery calcium was 1.32 (95% CI 1.04-1.68; P=0.02), after multivariable adjustment.

In BioImage, for every standard-deviation increase in the genetic risk score, there was a 9.7% increase (95% CI 2.2%–17.8%; P=0.01) in carotid artery plaque burden, after multivariable adjustment.

The researchers previously showed that a high genetic risk score was associated with a high risk of CHD, regardless of whether a person had a family history of cardiovascular disease, Natarajan noted.

The current study identified a subset of individuals more likely to have clinical benefit from a preventive strategy, which is a key goal of precision medicine, the researchers point out.

"This [study] says that among individuals at high risk [of CHD], if you're thinking about employing pharmacotherapy at this point, individuals at high genetic risk [of CHD] are more likely to benefit from that strategy," Natarajan summarized. However, the findings need to be confirmed in a prospective randomized trial.

A healthy lifestyle is important even in people with a high genetic risk of CHD. Although this genetic test can identify people at high risk of CHD, other factors that can influence CHD can substantially modify that risk, "so individuals that adhere to a healthy lifestyle, regardless of genetic risk, can further lower their risk of coronary heart disease," he said.

The study authors were supported by a John S LaDue Memorial Fellowship from Harvard Medical School, an Ofer and Shelly Nemirovsky Research Scholar Award from Massachusetts General Hospital, and grants from the National Institutes of Health. Natarajan reports receiving consulting fees from Amarin. Disclosures for the coauthors are listed in the paper.

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