Influence of LDL receptor gene mutations and the R3500Q mutation of the apoB gene on lipoprotein phenotype of familial hypercholesterolemic patients from a South European population.

Few data are available on genotype-phenotype interactions among familial hypercholesterolemia (FH) patients in South European populations and there are no data about the influence of R3500Q mutation on lipoprotein phenotype compared to low-density lipoprotein receptor (LDLR) mutations. The objective of the study is to analyze the influence of mutations in the LDLR and apolipoprotein B (apoB) genes on lipoprotein phenotype among subjects clinically diagnosed of FH living in East Spain. In all, 113 FH index patients and 100 affected relatives were studied. Genetic diagnosis was carried out following a protocol based on Southern blot and PCR-SSCP analysis. A total of 118 FH subjects could be classified into three groups according to the type of LDLR mutations (null mutations, missense mutations affecting the ligand binding 3-5 repeat, and missense mutations outside this domain). In addition, the lipoprotein phenotype of these FH groups was compared with 19 heterozygous subjects with familial ligand-defective apoB (FDB), due to R3500Q mutation. FH patients carrying missense mutations affecting the ligand binding repeat 3-5 showed total and LDL cholesterol levels significantly higher than FH patients with missense mutations in other LDLR domains or FDB patients. FH subjects carrying null mutations showed lower high-density lipoprotein cholesterol plasma values compared to FH carrying missense mutations. FDB subjects showed the lowest total and LDL cholesterol plasma values. In conclusion, the type of LDLR gene mutation and R3500Q mutation influences the lipoprotein phenotype of FH population from East Spain.

[Influence of plasma lipids, APOE genotype and type of LDL receptor gene mutations on myocardial infarction in subjects with familial hypercholesterolemia]. / Asociación de factores lipídicos, genotipo de APOE y tipos de mutación del gen del receptor de LDL con el infarto agudo de miocardio en sujetos con hipercolesterolemia familiar heterocigota.

BACKGROUND: Our goal was to analyze the relationship of lipids and lipoproteins, APOE genotype and mutations of the LDL receptor gene with the prevalence of myocardial infarction (MI) in patients with familial hypercholesterolemia (FH) from a Southern European FH population. PATIENTS AND METHOD: We studied 108 heterozygous FH subjects aged > 35 years (41 males). It was a cross-sectional study comparing individuals with FH and MI with individuals with FH without MI. In 88 FH subjects, a mutation of the LDL receptor gene was detected. These FH subjects were divided in carriers of null mutation or no null mutations. We compared lipids and lipoproteins and prevalences of LDL receptor type mutation and APOE genotype. RESULTS: Parameters associated with MI were: age, presence of xanthomas and arcus cornealis, plasma concentrations of total cholesterol (TC), LDLc, TC/HDLc ratio > 5.3 and *4 genotype of the APOE gene. Odds ratio for MI were as follows: presence of xanthomas and arcus cornealis, 1.36 (CI 95%, 1.08-1.71; P = 0.01), age > 54 years (50 th of FH group), 1.56 (CI 95%, 1.19-2.04; P = 0.001) and plasma TC values > 332 mg/dl (50 th of FH group), 1.34 (CI 95%, 1.05-1.71; P = 0.019). In the logistic regression model, only age and TC were significantly associated with MI. CONCLUSIONS: In FH subjects aged over 35 years from a Southern European population, MI is associated with age, plasma TC and LDLc values, TC/HDLc ratio and the *4 genotype. In addition, MI is related with age and TC plasma levels on an independent basis.