Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 2, Issue 4, Pages 354-U112Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.108.828467
Keywords
PCSK9; LDL-C; genetic variant; longitudinal study
Funding
- National Heart, Lung, and Blood Institute, National Institutes of Health [N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050]
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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. (Circ Cardiovasc Genet. 2009; 2: 354-361.)
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