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.