title: Contribution of receptor negative versus receptor defective mutations in the LDL-receptor gene to angiographically assessed coronary artery disease among young (25-49 years) versus middle-aged (50-64 years) men.
abstract: Elevated plasma LDL-cholesterol (LDL-C) levels are associated with an increased risk of coronary artery disease (CAD). Familial hypercholesterolemia (FH), a monogenic trait due to mutations in the LDL-receptor (R) gene is characterized by raised plasma LDL-C levels and premature CAD. The aim of the present investigation, derived from the study of a population of 1465 unrelated men aged 25 to 64 years, was to compare the expression of CAD assessed by coronary angiography in young (aged 25-49 years) versus middle-aged (50-64 years) heterozygous FH patients of French Canadian descent. Furthermore, the relationship of binding-defective versus receptor negative mutations in the LDL-R to premature CAD ( < 50 years) was examined and compared with men displaying a normal plasma lipoprotein-lipid profile. From the original study sample, a total of 100 men met the clinical criteria of heterozygous FH. Among them, 30 were carriers of a receptor negative mutation (deletion > 15 kb or point mutations Y468X or R329X) whereas 64 were carriers of a receptor defective mutation (W66G, E207K or C646Y). As expected, in both age groups (25-49 years vs. 50-64 years), carriers of a receptor negative mutation had higher plasma cholesterol and LDL-C levels than carriers of a defective allele or men with a normal plasma lipoprotein-lipid profile. In addition, the mean number of diseased vessels (with > 50% stenosis) was higher in men aged 50-64 years compared to those aged 25 49 years. In the two age groups, FH patients were characterized by a higher number of stenosed coronary vessels than the normal phenotype group. Within each group (either receptor negative, receptor defective or normal phenotype) plasma cholesterol, LDL-C, HDL-C, triglyceride and apolipoprotein B levels were similar irrespective of age (25 49 years vs. 50-64 years). Finally, multiple logistic regression analyses revealed that compared to non-FH men, the relative odds of being affected by CAD before the age of 50 years was 7.3-fold higher for carriers of a receptor negative mutation and 2.7-fold higher for men with a receptor defective mutation at the LDL-R locus. These results suggest that CAD could be an earlier event among heterozygous FH subjects bearing a receptor negative mutation compared to LDL-R defective patients. It also suggest that the selective screening for mutations in the LDL-R gene may allow a better assessment of the individual risk and facilitate the development of family-based preventive strategies or intervention programs in FH.
authors: Chicoutimi Hospital Lipid Clinic, Quebec, Canada. dgaudet@saglac.qc.ca
authors: D
authors: D
authors: Gaudet
authors: M C
authors: MC
authors: Vohl
authors: P
authors: P
authors: Couture
authors: S
authors: S
authors: Moorjani
authors: G
authors: G
authors: Tremblay
authors: P
authors: P
authors: Perron
authors: C
authors: C
authors: Gagné
authors: J P
authors: JP
authors: Després
mesh_terms: D000328:Adult; D000367:Age Factors; D017023:Coronary Angiography; D003327:Coronary Disease / Q000097:blood / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D005602:France / Q000208:ethnology; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000235:genetics; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011792:Quebec; D011973:Receptors, LDL / Q000235:genetics*; D012307:Risk Factors
chemical_list: D008055:Lipids; D008074:Lipoproteins; D011973:Receptors, LDL