Long-term genetically low levels of LDL cholesterol, by means of functional variants in the PCSK9 gene, were associated with a reduced risk of CV mortality, but not all-cause mortality, in a large cohort of individuals.

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“We tested the hypothesis that genetically low LDL cholesterol due to PCSK9 [proprotein convertase subtilisin/kexin type 9] variation is causally associated with low cardiovascular and all-cause mortality in a general population of Northern European ancestry,” wrote Marianne Benn, MD, DMSc, and colleagues. The findings were published in the Journal of the American College of Cardiology.

The researchers conducted a large-scale genetic analysis of 109,566 persons from the Copenhagen City Heart Study and Copenhagen General Population Study. In addition, the team included a validation cohort of 431,043 individuals from the UK Biobank.

The median duration of follow-up was 10 years (0-42 years), and the median age at study entry was 57 years.

Study participants were genotyped for several PCSK9 variants and a weighted allele score based the effects of LDL cholesterol, individual allele frequency, and number of variant alleles was calculated for each subject.

Weighted scores were categorized into five stepwise noncontinuous score ranges, with lower levels of LDL cholesterol linked to higher allele scores.

After analysis, the researchers found that a growing number of PCSK9 alleles were associated with lower levels of LDL cholesterol up to 0.61 mmol/L (P for trend less than .001) and reduced CV mortality (P = .001), but not with reduced all-cause mortality (P = .11).

“Our genetic data did not show a reduction in risk of all-cause mortality, and only showed a reduction in risk of all-cause mortality in statin trials and not in the PCSK9-inhibitor trials meta-analyzed,” the researchers wrote. “This may be explained by the low frequency of cardiovascular disease in the 2 populations studied,” they explained.

One key limitation was the homogeneous makeup of the study population. Dr. Benn and colleagues acknowledged this could limit the generalizability of the results.

“Long-term LDL cholesterol treatment (e.g., with PCSK9 inhibitors), may translate into reductions in cardiovascular mortality,” they concluded.

The study was supported by the Danish Council for Independent Research, Medical Sciences, Johan Boserup, and the Lise Boserup’s Fund. The authors reported no conflicts of interest.

SOURCE: Benn M et al. JACC. 2019 Jun 17. doi: 10.1016/j.jacc.2019.03.517