LPA Variants Linked With CHD Events in Statin-Treated Patients

In a large group of individuals treated with statin therapy, seven single nucleotide polymorphisms (SNPs) on the LPA gene were associated with a significantly increased risk of coronary heart disease (CHD), according to the results of a new genome-wide association study.

Even among patients who achieved excellent on-treatment LDL cholesterol levels, the heightened risk of CHD for those with the LPA variants remained statistically significant, suggesting that future strategies targeting lipoprotein(a)—the LPA gene encodes Lp(a)—might be helpful in lowering the residual risk of patients already treated with statins.

“There are a number of patients taking statins who still develop cardiovascular events,” lead investigator Wei-Qi Wei, MD, PhD (Vanderbilt University Medical Center, Nashville, TN), told TCTMD. “We wondered what happens, and [wanted] to compare why some patients taking statins still have some risk while other patients taking statins don’t have any CVD risk at all. We thought there might be some genetic reason behind this.”

The study, which was published recently in Circulation, is based on data from the eMERGE network, a consortium of US cohorts with DNA samples linked to electronic health records. In addition to studying cases and controls identified at four eMERGE sites, the researchers genotyped an additional cohort obtained from BioVU, a DNA databank at Vanderbilt University. Cases and controls from the Partners HealthCare Biobank served as the validation cohort.

LPA Link Even Among Well-Treated Patients

In total, 3,099 individuals on statin therapy with CHD events and 7,681 controls were included in the analysis. The replication cohort from the Partners databank included 160 cases with CHD and 1,112 controls. Overall, the people included in the eMERGE and BioVU cohorts were mostly identified as white and ranged in age from 68 to 83 years old. Average LDL cholesterol levels ranged from 87 mg/dL to 113 mg/dL.

The genome-wide association study identified seven SNPs within the LPA/PLG locus that were linked with CHD events while on statin therapy. There were five SNPs located on the LPA gene, one SNP located on the PLG gene, which encodes for plasminogen, and one encompassing the LPA/PLG region.

For the SNP with the most significant association, those who carried the minor allele were more likely than noncarriers to have CHD events on statin therapy (OR 1.58; 95% CI 1.35-1.86). In the replication cohort, this SNP was also associated with an increased risk of CHD events among patients treated with statins (OR 1.71; 95% CI 1.14-2.57). The LPA locus was associated with an increased risk of CHD events independent of the changes in LDL cholesterol, and the link was also observed among individuals with an LDL cholesterol level 70 mg/dL or lower.

The “big news” from their analysis is that the SNPs on the LPA gene were a risk factor for CHD events independent of statin therapy, said Wei. “Traditionally, we know Lp(a) is associated with LDL cholesterol and we target LDL cholesterol to reduce cardiovascular events,” he said. “This paper shows that even in some patients treated with statins, we might still consider Lp(a) as another potential target.”

To TCTMD, Wei said that roughly 6% to 7% of Caucasian individuals with European ancestry carry the minor allele for the SNP that has the strongest association to CHD risk.

From a clinical perspective, Michael Blaha, MD (Johns Hopkins Medicine, Baltimore, MD), who was not involved in the study, said he will measure Lp(a) in patients with early cardiovascular disease or in patients with a strong family history of cardiovascular disease. “This helps me identify patients that are higher risk than I might have otherwise expected, and I might shoot for an even lower LDL target in these patients,” he said. “However, it is not really possible to ‘target’ Lp(a) right now since we don’t have specific agents that selectively lower Lp(a).”

Niacin lowers Lp(a), but has never been shown to reduce the risk of cardiovascular events, and PCSK9 inhibitors lower Lp(a) to a small extent, he said.   

Clinical and Research Implications

Christie Ballantyne, MD (Baylor College of Medicine, Houston, TX), who also commented on the study, said that high levels of Lp(a) and its genetic variants are known to be associated with an increased risk of developing cardiovascular events, a finding confirmed in “study after study.”

“The big question—and this is relevant to clinical progress in the field—is if we’re going to test therapies for lowering Lp(a), in whom should they be tested?” asked Ballantyne. “Obviously, if you’re going to do this, you want people with a high event rate. . .With any new therapy, you want a high-risk population to test it in, and it’s going to be on top of background statin therapy. Presumably, most people will be getting aspirin as well if it’s a secondary prevention population.”

An antisense oligonucleotide is currently in development for targeting Lp(a). The agent belongs to a class of RNA therapeutic drugs designed to selectively bind mRNA coding for specific proteins. In this case, the antisense therapy reduces the production of the apo(a) protein in the liver and reduces Lp(a).

Rather than observational studies, Ballantyne said the residual risk associated with Lp(a) might be best studied in large clinical trials, such as IMPROVE-IT, ODYSSEY-Outcomes, and FOURIER, because these are high-risk patients optimized on medical therapy. He pointed out that previous analyses have been mixed so far. For example, an analysis of the dal-OUTCOMES trial showed no association between Lp(a) and risk of cardiovascular events, while an analysis of the SATURN trial found no association between high levels of Lp(a) and the progression of atherosclerosis as measured on IVUS.

Ballantyne added that the present study is limited in that it did not assess the risk associated with circulating Lp(a) levels, only by genetic variants. “This study is encouraging in that there is a substantial amount of residual risk,” he said, but noted “it’s still not clear who are the people with highest risk driven by high Lp(a) that we should be studying in clinical trials.”

Ultimately though, Ballantyne believes Lp(a) is a very important risk factor, one that is widely underappreciated. “If you look at people with premature heart disease, very frequently they have high Lp(a),” he said, “and it’s not being screened in family members.”

Blaha, who said Lp(a) accounts for at least some of residual risk of clinical events outside of traditional risk factors, said he will use it to guide cascade testing in family members. “I imagine in the future a day when I use Lp(a) levels to guide selective use of specific Lp(a)-lowering therapies, should these novel agents reduce cardiovascular events in well-designed cardiovascular outcomes trials,” he said.