Published Online
on June 10, 2009

A more recent version of this article appeared on August 1, 2009

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Original Article

Longitudinal Association of PCSK9 Sequence Variations with LDL-Cholesterol Levels: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Chiang–Ching Huang¹; Myriam Fornage²; Donald M. Lloyld–Jones¹; Gina S. Wei³; Eric Boerwinkle² and Kiang Liu^1,4

¹ Northwestern University, Chicago, IL;
² University of Texas Health Science Center, Houston, TX;
³ The National Heart, Lung, and Blood Institute, Bethesda, MD

⁴ E-mail: kiangliu{at}northwestern.edu

Background—Mutations of PCSK9 are associated cross-sectionally with plasma LDL 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 African Americans and 1828 whites from the CARDIA study. Generalized estimating equations were used to assess longitudinal differences in LDL-C levels between genotype categories. For African Americans, 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 non-carriers (109.6 mg/dL). The difference in LDL-C levels from non-carriers 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 non-carriers, LDL-C levels at age 18 were significantly lower (84.4 vs 100.9 mg/dL, p<0.001), and the increase in LDL-C with age was similar to non-carriers. The 3 genetic variants and the A443T variant in African American men were associated with lower carotid intima-media thickness and lower prevalence of coronary calcification measured at ages 3850.

Conclusions—Our results suggest that participants with several genetic variants of PCSK9 have persistently lower serum LDL-C levels than non-carriers from ages 18-50. Such long-term reduction in LDL-C levels is associated with reduced subclinical atherosclerosis burden in African-American men.

Key Words: genetics • LDL-C • PCSK9 • longitudinal study