Relation of PCSK9 mutations to serum low-density lipoprotein cholesterol in childhood and adulthood (from The Bogalusa Heart Study).
Specific mutations in the gene for proprotein convertase, subtilisin-kexin type 9 (PCSK9), that are associated with lower coronary heart disease risk may produce lifelong decreases in low-density lipoprotein (LDL) cholesterol levels, but data on their effects in younger subjects are lacking. We analyzed associations of 1 missense (R46L) and 2 nonsense (Y142X and C679X) PCSK9 mutations with serum LDL cholesterol in 478 African-Americans and 1,086 whites, 4 to 38 years of age, examined 3 to 8 times in the Bogalusa Heart Study. L46 allele frequency in whites was 0.017 +/- 0.003; the combined frequency of X142 or X679 alleles in African-Americans was 0.016 +/- 0.005. In whites, LDL cholesterol was lower in L46 carriers (78.9 +/- 21.8 mg/dl) than in noncarriers (89.7 +/- 24.9 mg/dl, p = 0.027) at their first examination (mean age 9.4 +/- 3.2 years). African-Americans carrying the X142 or X679 allele had lower LDL cholesterol levels than did noncarriers (77.3 +/- 15.1 vs 91.4 +/- 23.9 mg/dl, p = 0.043) at their first examination (mean age 9.0 +/- 3.0 years). Longitudinal LDL cholesterol profiles were significantly lower in whites with the L46 allele and in African-Americans with the X142 or X679 allele. In conclusion, our results show that these PCSK9 variants are associated with significantly lower LDL cholesterol levels starting in childhood.
Hallman
D Michael
DM
Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA. d.michael.hallman@uth.tmc.edu
Srinivasan
Sathanur R
SR
Chen
Wei
W
Boerwinkle
Eric
E
Berenson
Gerald S
GS
D001741:Black or African American; D000483:Alleles; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D018389:Codon, Nonsense; D003327:Coronary Disease / Q000208:ethnology / Q000235:genetics*; D005260:Female; D006801:Humans; D008145:Louisiana / Q000453:epidemiology; D008297:Male; D020125:Mutation, Missense; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics*; D044465:White People
D008078:Cholesterol, LDL; D018389:Codon, Nonsense; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases