PCSK9 gene genotype influences LDL levels, heart disease risk
MedWire News: A variant in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) is associated with reduced levels of low-density lipoprotein (LDL) cholesterol and a reduced risk for ischemic heart disease (IHD), a major study has found.
Researchers led by Anne Tybjærg-Hansen (Copenhagen University Hospital, Denmark) conducted a series of analyses to assess the effect of the PCSK9 R46L allele on LDL cholesterol and IHD-related outcomes.
First, they tested these associations within three separate cohorts: The prospective population-based Copenhagen City Heart Study (n=10,032); the cross-sectional Copenhagen General Population Study (n=26,013); and the case–control Copenhagen Ischemic Heart Disease Study (n=9654).
In these studies, LDL cholesterol levels were 11–16% lower in 46L allele carriers versus noncarriers, the team reports in the Journal of the American College of Cardiology.
The observed risk-reductions in IHD ranged from 6% to 46% for 46L carriers versus noncarriers. However, the risk for mortality or IHD mortality in one study was not influenced by PCSK9 genotype.
Interestingly, the reduction in IHD risk associated with the 46L allele was much larger than predicted by LDL cholesterol levels alone, at 28% observed versus 5% predicted.
“This could be because genotype is a better predictor of lifelong exposure to LDL cholesterol than LDL cholesterol measured in adult life,” the authors speculate.
They then performed a meta-analysis of seven general population studies with a total of 1639 46L carriers and 59,198 noncarriers.
In this pooled analysis, mean LDL cholesterol levels were 12% lower in 46L allele carriers versus noncarriers, while the risk-reduction in IHD ranged from 23% to 28%.
Tybjærg-Hansen et al conclude: “The PCSK9 46L allele was associated with reductions in LDL cholesterol of 11% to 16% in all age groups from 20 to 80+ years in the general population.
“The 30% reduction in risk of IHD observed in our three studies combined was larger than predicted by the reduction in LDL cholesterol alone.”
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By Joanna Lyford