Lp(a) Genetics Differ Between Populations but Have Similar Clinical Impact

Although the genes that affect lipoprotein(a) in European and East Asian populations might vary, the downstream clinical effects that stem from high Lp(a) levels are similar, according to data from the United Kingdom and China.

The findings have larger implications for ongoing trials of novel medications that lower Lp(a) than they do on current clinical practice, say researchers. Lp(a)HORIZON with the antisense therapy pelacarsen (Novartis), and the ACCLAIM-Lp(a) and OCEAN(a) trials with the small-interfering RNA therapies lepodisiran (Eli Lilly) and olpasiran (Amgen), respectively, are currently underway to gauge their effects on hard endpoints like coronary heart disease (CHD) and stroke.

These new data are “relevant if you are comparing the results of one agent that is an antisense [inhibitor] versus an siRNA,” lead author Robert Clarke, MD (University of Oxford, England), told TCTMD. “You'd like to know that the Lp(a) in the Asians behaves the same way as in the Europeans and [that] any differences between the trial results were not due to the fact that they included [different populations].”

The main message for clinicians, he said, is to pay attention to the absolute level of Lp(a) in patients, not the genetics that may have caused it. Guillaume Paré, MD (McMaster University, Hamilton, Canada), who was not involved in the study, agreed.

“The genetics might be different, but at the end of the day, it carries the same risk of disease, and therefore we can expect that decreasing Lp(a) will carry the same benefit irrespective of ancestry,” he told TCTMD. “That's very reassuring and very encouraging for the clinical development of the lipoprotein(a) inhibitors.”

China Kadoorie and UK Biobanks

Observational and genetic studies of Lp(a) have linked elevated levels to an increased risk of CHD, stroke, and aortic stenosis. Largely genetically determined, Lp(a) is considered a risk-enhancing factor in clinical guidelines and it’s recommended that clinicians check levels at least once during a patient’s lifetime. Right now, though, there is no approved treatment for lowering Lp(a) levels.

While the genetic underpinnings of elevated Lp(a) have been well characterized in several European cohorts, less is known about the genetics in non-Europeans.

For the new study, published online last week in Circulation, researchers assessed the genetic causes of Lp(a) in a large East Asian cohort as well as a European cohort and evaluated the association between Lp(a) and clinical outcomes. The analysis included measured Lp(a) levels in 18,174 adults (mean age 57 years; 49% female) from two populations: the China Kadoorie Biobank and the UK Biobank.

In genome-wide association analyses, 29 single-nucleotide polymorphisms (SNPs) were independently linked to Lp(a)—explaining 33% of the variance—in Chinese adults. These variants also were found among adults in the UK, where they explained 10% of the variance, but there was only modest overlap between the two cohorts.  

In mendelian randomization analyses, the effect sizes of Lp(a) on hard outcomes were highly comparable in both groups. When the populations were combined, each reduction in Lp(a) of 100 nmol/L was associated with a lower risk of ischemic stroke (rate ratio [RR] 0.78; 95% CI 0.76-0.81), large-artery ischemic stroke (RR 0.80; 95% CI 0.73-0.87), and MI (RR 0.94; 95% CI 0.92-0.96).

Reductions in Lp(a) weakly correlated with a lower risk of cardioembolic ischemic stroke but had no effect on small-vessel ischemic stroke or intracerebral hemorrhage.

In East Asian populations, stroke has become an increasingly larger issue, Clarke said, and there has been a “lack of appreciation of the heterogeneity in stroke types.” It appears that lowering Lp(a) is not going to help decrease the risk of small-vessel as much as large-artery strokes, he said.

Because of this, if the primary endpoint of the ongoing trials of Lp(a)-lowering agents include all strokes, there might be a “dilution” in any differences. As such, Clarke hopes to see these studies include prespecified individual-level meta-analyses of all the data as well as prespecify two primary outcomes for both “CHD and stroke associated with a standardized differences in Lp(a)-lowering by 100 nmol/L.”

According to Paré, the study highlights how “we cannot blindly apply the [genetic] findings from one population to another.” He called for similar studies to be conducted in “all populations of the world,” especially in adults with African and South Asian ancestry. But what the data mostly confirm, he continued, is the need to prioritize screening to identify patients with the highest Lp(a) levels, regardless of their genetics, and to eventually offer them treatment.