Published online before print June 10, 2009, doi: 10.1161/CIRCGENETICS.108.828467
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Original Articles |
Longitudinal Association of PCSK9 Sequence Variations With Low-Density Lipoprotein Cholesterol Levels
The Coronary Artery Risk Development in Young Adults Study
From the Department of Preventive Medicine (C.C.H., D.M.L.-J., K.L.), Feinberg School of Medicine, Northwestern University, Chicago, Ill; Brown Foundation Institute of Molecular Medicine (M.F., E.B.) and Human Genetics Center (E.B.), University of Texas Health Science Center, Houston, Tex; and Division of Prevention and Population Sciences (G.S.W.), The National Heart, Lung, and Blood Institute, Bethesda, Md.
Correspondence to Kiang Liu, PhD, 680 N Lake Shore Dr, Suite 1102, Chicago, IL 60611. E-mail kiangliu{at}northwestern.edu
Received October 13, 2008; accepted May 27, 2009.
Background— Mutations of PCSK9 are associated cross-sectionally with plasma low-density lipoprotein cholesterol (LDL-C) levels, but little is known about their longitudinal association with LDL-C levels from young adulthood to middle age.
Methods and Results— We investigated the associations of 6 PCSK9 variants with LDL-C over 20 years in 1750 blacks and 1828 whites from the Coronary Artery Risk Development In Young Adults study. Generalized estimating equations were used to assess longitudinal differences in LDL-C levels between genotype categories. For blacks, LDL-C levels at age 18 were significantly lower (P<0.001) among those with 3 genetic variants (L253F, C679X, and Y142X; 81.5 mg/dL) and A443T (95.5 mg/dL) compared with noncarriers (109.6 mg/dL). The difference in LDL-C levels from noncarriers tended to widen for those with the 3 variants only, by 0.24 mg/dL per year of age (P=0.14). For whites with the R46L variant, compared with noncarriers, LDL-C levels at age 18 were significantly lower (84.4 mg/dL versus 100.9 mg/dL; P<0.001), and the increase in LDL-C with age was similar to noncarriers. The 3 genetic variants and the A443T variant in black men were associated with lower carotid intima-media thickness and lower prevalence of coronary calcification measured at ages 38 to 50.
Conclusions— Our results suggest that participants with several genetic variants of PCSK9 have persistently lower serum LDL-C levels than noncarriers from ages 18 to 50. Such long-term reduction in LDL-C levels is associated with reduced subclinical atherosclerosis burden in black men.
Key Words: PCSK9 • LDL-C • genetic variant • longitudinal study
CLINICAL PERSPECTIVE
The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.828467/DC1.