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.
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.
Authors: Kirsten M Timms; Susanne Wagner; Mark E Samuels; Kristian Forbey; Howard Goldfine; Srikanth Jammulapati; Mark H Skolnick; Paul N Hopkins; Steve C Hunt; Donna M Shattuck Journal: Hum Genet Date: 2004-01-15 Impact factor: 4.132
Authors: J Jeffrey Carr; Jennifer Clark Nelson; Nathan D Wong; Michael McNitt-Gray; Yadon Arad; David R Jacobs; Stephan Sidney; Diane E Bild; O Dale Williams; Robert C Detrano Journal: Radiology Date: 2005-01 Impact factor: 11.105
Authors: Jonathan Cohen; Alexander Pertsemlidis; Ingrid K Kotowski; Randall Graham; Christine Kim Garcia; Helen H Hobbs Journal: Nat Genet Date: 2005-01-16 Impact factor: 38.330
Authors: Jay D Horton; Nila A Shah; Janet A Warrington; Norma N Anderson; Sahng Wook Park; Michael S Brown; Joseph L Goldstein Journal: Proc Natl Acad Sci U S A Date: 2003-09-25 Impact factor: 11.205
Authors: Donald M Lloyd-Jones; Peter W F Wilson; Martin G Larson; Eric Leip; Alexa Beiser; Ralph B D'Agostino; James I Cleeman; Daniel Levy Journal: Arch Intern Med Date: 2003-09-08
Authors: D H O'Leary; J F Polak; R A Kronmal; P J Savage; N O Borhani; S J Kittner; R Tracy; J M Gardin; T R Price; C D Furberg Journal: Stroke Date: 1996-02 Impact factor: 7.914
Authors: G D Friedman; G R Cutter; R P Donahue; G H Hughes; S B Hulley; D R Jacobs; K Liu; P J Savage Journal: J Clin Epidemiol Date: 1988 Impact factor: 6.437
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Authors: Ching-Wei Tsai; Kari E North; Adrienne Tin; Karin Haack; Nora Franceschini; V Saroja Voruganti; Sandy Laston; Ying Zhang; Lyle G Best; Jean W MacCluer; Terri H Beaty; Ana Navas-Acien; W H Linda Kao; Barbara V Howard Journal: J Clin Endocrinol Metab Date: 2014-11-20 Impact factor: 5.958
Authors: Marc A Coram; Qing Duan; Thomas J Hoffmann; Timothy Thornton; Joshua W Knowles; Nicholas A Johnson; Heather M Ochs-Balcom; Timothy A Donlon; Lisa W Martin; Charles B Eaton; Jennifer G Robinson; Neil J Risch; Xiaofeng Zhu; Charles Kooperberg; Yun Li; Alex P Reiner; Hua Tang Journal: Am J Hum Genet Date: 2013-05-30 Impact factor: 11.025