Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
BACKGROUND
A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population.


METHODS
We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol.


RESULTS
Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003).


CONCLUSIONS
These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.
Cohen
Jonathan C
JC
Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
Boerwinkle
Eric
E
Mosley
Thomas H
TH
Hobbs
Helen H
HH
D044383:Black People / Q000235:genetics; D002339:Carotid Arteries / Q000033:anatomy & histology; D008078:Cholesterol, LDL / Q000097:blood*; D018389:Codon, Nonsense; D015331:Cohort Studies; D003327:Coronary Disease / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007009:Hypolipoproteinemias / Q000235:genetics*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012306:Risk; D012697:Serine Endopeptidases / Q000235:genetics*; D014481:United States; D044465:White People / Q000235:genetics; D001741:Black or African American
D008078:Cholesterol, LDL; D018389:Codon, Nonsense; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases