Variation in PCSK9, low LDL cholesterol, and risk of peripheral arterial disease.
BACKGROUND
We hypothesized that variants in PCSK9 that lower LDL cholesterol levels are associated with reduced prevalence and incidence of peripheral artery disease (PAD).


METHODS
The Atherosclerosis Risk in Communities (ARIC) Study assessed risk factors and PCSK9 variants Y142X and C679X (relevant to blacks) and R46L (relevant to whites) in a cohort of 45-64-year olds in 1987-1989 (n=13,634). Prevalent PAD (n=619 cases) was defined by an ankle-brachial index <0.9 or a history of leg claudication. Incident PAD (n=895) was identified from 1987 to 1998 by the same PAD criteria or a PAD hospitalization.


RESULTS
As expected, greater LDL cholesterol was a risk factor for prevalent and incident PAD. 2.4% of blacks and 3.1% of whites were carriers of one of the race-specific PCSK9 variants. Carriers had lower prevalence of PAD compared with non-carriers (2.3% vs. 4.6%). The corresponding age- and sex-adjusted odds ratio of PAD was 0.47 (95% confidence interval, 0.24-0.92). In contrast with the cross-sectional findings, there was no association between PCSK9 variants and incident PAD (age- and sex-adjusted hazard ratio, 1.09 (95% confidence interval, 0.76-1.57)).


CONCLUSIONS
Our study provides mixed evidence that variation in PCSK9 may contribute to genetic risk of PAD.
Folsom
Aaron R
AR
Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, United States. folsom@epi.umn.edu
Peacock
James M
JM
Boerwinkle
Eric
E
D008078:Cholesterol, LDL / Q000378:metabolism*; D015331:Cohort Studies; D005006:Ethnicity; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D016491:Peripheral Vascular Diseases / Q000097:blood* / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D015995:Prevalence; D016016:Proportional Hazards Models; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012306:Risk; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics*
D008078:Cholesterol, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases