Genetic Variations Increase Heart Attack Risk for Statin Patients

Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with HMG-CoA reductase inhibitors (statins) decreases circulating levels of low-density lipoprotein cholesterol (LDL-C) and the incidence of CHD, additional events occur despite statin therapy in some individuals.

Genetic variations have been discovered that increase the risk of heart attack even when patients are receiving a statin drug to lower their blood cholesterol. This may help to explain why some patients experience a heart attack or the need for coronary revascularization to open blocked heart arteries while taking statins. The discovery suggests that drugs targeting the genetic variations could lower the heart risk in these patients.

A large team of scientists led by those at Vanderbilt University Medical Center (Nashville, TN, USA) performed a two-stage genome-wide association study (GWAS) of CHD events during statin therapy. They first identified 3,099 cases that experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7,681 controls without CHD events during comparable intensity and duration of statin therapy. They then sought replication of candidate variants in another 160 cases and 1,112 controls performed a phenome-wide association study (PheWAS) for other traits linked to the most significant locus.

The investigators were able to identify seven genetic variations, called single nucleotide polymorphisms or SNPs, in the Lipoprotein(A) (LPA) locus of genes that were associated with these heart events in patients receiving statin treatment. The LPA gene encodes apolipoprotein (a), a fatty protein that binds to low-density lipoprotein (LDL), the form of blood cholesterol that is the target of statin drugs. High levels of bound LDL, called Lp(a) for short, is well known to be an independent risk factor for heart disease.

One of the SNPs was highly associated with an increased risk of heart events. When the team examined the full electronic health records (EHRs) of 11,566 individuals who carried the SNP for more than 1,000 physical conditions, they found significantly higher rates of coronary heart disease and heart attack but not of other diseases. Joshua C. Denny, MD, MS, a Professor of Biomedical Informatics and Medicine and a leading author of the study, said, “People with these genetic variants were at a higher risk for heart disease, even considering those who have ideal cholesterol levels on their statin.”

The authors concluded that a genetic variation at the LPA locus is associated with CHD events during statin therapy independent of the extent of LDL-C lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins. The study was published on April 27, 2018, in the journal Circulation.

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Vanderbilt University Medical Center