Genotype of the mutant LDL receptor allele is associated with LDL particle size heterogeneity in familial hypercholesterolemia.
Small, dense LDL particles have been associated with an increased risk of coronary artery disease. In order to assess the potential contribution of the genotype of the LDL receptor to LDL particle size heterogeneity in familial hypercholesterolemia (FH), we examined the electrophoretic characteristics of LDL particles in a large cohort of FH heterozygotes and controls. A total of 259 FH heterozygotes and 208 controls participated in the study. FH subjects were carriers of one of the nine French Canadian mutations in the LDL receptor gene. LDL particles were characterized by polyacrylamide gradient gel electrophoresis following a 6-week lipid-lowering drug-free baseline period. LDL-peak particle diameter (LDL-PPD), representing the most abundant LDL particle subpopulation, was significantly smaller in FH heterozygotes carrying a negative-receptor mutation than in subjects carrying a defective-receptor mutation (negative-receptor = 257.3 +/- 4.1 A versus defective-receptor = 259.0 +/- 4.3 A, p = 0.0006). No significant difference in plasma CETP concentrations was found between these two genotypic groups. Moreover, compared with controls having low triglyceride levels, negative-receptor subjects with high triglyceride levels had a relative risk of 19.6 (p < 0.0001) of having small, dense LDL particles while this risk was not significantly increased among defective-receptor subjects. Multivariate analysis showed that the LDL receptor status accounted for 5.7% of the variance in the LDL-PPD after adjustment for covariates. These results suggest that the genotype of the mutant LDL receptor allele was independently associated with variations in LDL-PPD and could partly explain why negative-receptor FH heterozygotes may be at greater risk of cardiovascular disease than defective-receptor FH subjects.
Hogue
Jean-Charles
JC
Lipid Research Center (S-102), CHUL Research Center, Laval University, Qué., G1V 4G2, Canada.
Lamarche
Benoît
B
Gaudet
Daniel
D
Tremblay
André J
AJ
Després
Jean-Pierre
JP
Gagné
Claude
C
Couture
Patrick
P
D000328:Adult; D000483:Alleles; D015139:Blotting, Southern; D002352:Carrier Proteins / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL / Q000097:blood / Q000737:chemistry*; D004247:DNA / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006023:Glycoproteins / Q000097:blood; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood* / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D011973:Receptors, LDL / Q000235:genetics*; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood
C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL; D006023:Glycoproteins; D011973:Receptors, LDL; D014280:Triglycerides; D004247:DNA