Coronary Artery Disease in Heterozygous Familial Hypercholesterolemia Patients With the Same LDL Receptor Gene Mutation

BACKGROUND: Familial hypercholesterolemia (FH), an autosomal codominant disease, is characterized by high levels of LDL cholesterol and a high incidence of coronary artery disease (CAD). To date, genetic heterogeneity has hindered the proper assessment of the relation between risk factors and CAD in FH patients. METHODS AND RESULTS: We studied the association between CAD and common risk factors in a sample of 263 French Canadian FH patients (147 women, 116 men) carrying the same > 10-kb deletion of the LDL receptor gene. Thirty-five women and 54 men had CAD. The mean age of onset of CAD was 45.6 +/- 12.7 years in women and 38.8 +/- 9.4 years in men. Multiple logistic regression analyses were performed to test the association between CAD and age, tendon xanthomas, cigarette smoking, hypertension, diabetes mellitus, apolipoprotein E polymorphism, total plasma cholesterol, triglycerides, VLDL cholesterol, LDL cholesterol, HDL cholesterol, and lipoprotein(a) Lp(a). In FH women, significant multivariate predictors were age (odds ratio, 1.10 for 1 year; P < .0001), VLDL cholesterol (odds ratio, 3.85 for 1 natural log unit; P < .002), and LDL cholesterol (odds ratio, 1.42 for 1 mmol/L; P < .02). In FH men, age (odds ratio, 1.08 for 1 year; P < .0001) and HDL cholesterol (odds ratio, 0.14 for 1 mmol/L; P = .05) were significant predictors of disease. Lp(a) was not a significant predictor in univariate or multivariate analyses. CONCLUSIONS: This study suggests that increased risk of CAD in FH is not solely due to elevated LDL cholesterol levels and demonstrates a sex-specific lipoprotein influence on CAD in a large sample of FH patients carrying the same LDL receptor gene defect.