Low LDL Cholesterol by PCSK9 Variation Reduces Cardiovascular Mortality

Area of Science:

• Cardiovascular Genetics
• Molecular Biology
• Population Health

Background:

• Inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) lowers low-density lipoprotein (LDL) cholesterol, reducing cardiovascular events.
• This reduction in cardiovascular events may also decrease cardiovascular and all-cause mortality.

Purpose of the Study:

• To test if genetically low LDL cholesterol, due to PCSK9 variation, is causally linked to reduced cardiovascular and all-cause mortality in the general population.
• Investigate the causal association between PCSK9 genetic variations and mortality outcomes.

Main Methods:

• Genotyping of PCSK9 variants (R46L, R237W, I474V, E670G) in 109,566 individuals from the Copenhagen General Population Study and Copenhagen City Heart Study.
• Follow-up for a median of 10 years, recording cardiovascular and all-cause deaths.
• Validation of results using data from 431,043 individuals in the UK Biobank.

Main Results:

• An increasing number of weighted PCSK9 alleles correlated with progressively lower LDL cholesterol levels (up to 0.61 mmol/l).
• Lower LDL cholesterol was associated with reduced cardiovascular mortality (p=0.001).
• No significant association was found between genetically low LDL cholesterol and reduced all-cause mortality (p=0.11).

Conclusions:

• Genetically determined low LDL cholesterol, driven by PCSK9 variation, is causally associated with a lower risk of cardiovascular mortality in the general population.
• The study did not find a causal association between genetically low LDL cholesterol and reduced all-cause mortality.