No abstract

The aim of this study was the characterization of mutations of the LDL receptor gene in 39 Italian patients with homozygous familial hypercholesterolemia, who were examined during the period 1994 to 1996. The age of the patients ranged from 1 to 64 years; one third of them were older than 30. Plasma LDL cholesterol level ranged from 10.8 to 25.1 mmol/L. The residual LDL receptor activity, measured in cultured fibroblasts of 32 patients, varied from <2% to 30% of normal and was inversely correlated with the plasma LDL cholesterol level (r=-0.665; P<0.003). The most severe coronary atherosclerosis was observed in those patients with the lowest residual LDL receptor activity (

We have used four restriction fragment length polymorphisms (RFLPs) of the human low density lipoprotein receptor (LDL-R) gene, detected by the restriction enzymes Ava ILPVM IL and ApaU (5' and 3'), to study the effect of variation at this gene locus in determining plasma cholesterol and LDL cholesterol levels. Two hundred eighty-nine nonmolipidemic individuals were studied from the Liguria region of Italy. The Pvu M RFLP was significantly associated with differences in plasma total and LDL cholesterol levels, explaining 9.6% of the sample variance in LDL cholesterol levels. The other RFLPs, which are in strong linkage disequilibrium with the Pvu II RFLP, were associated with smaller effects on LDL cholesterol. The Pvu II allele, distinguished by the presence of the variable cutting site (P2 allele), was associated with lower levels of total and LDL cholesterol, and the frequency of the P2 allele was significantly reduced in individuals with LDL cholesterol levels higher than the 75th percentile. The frequency of the P2 allele was significantly higher in the group of individuals over 65 years old, and in this gronp the P2 allele was also associated with a similar reduction in LDL cholesterol levels. Because of linkage disequilibrium, only four RFLP haplotypes were common in this sample. Of these, only the haplotype P2A2VI (relative frequency, 0.269) was associated with a reduction in LDL cholesterol (average excess, -11.5 mg/dl). Our data confirm, in the Italian population, the association observed with the Pvu H RFLP by others, and the higher relative frequency of the LDL cholesterol-lowering P2 allele in individuals over the age of 65 years suggests that the allele may be associated with increased survival. (Arteriosclerosis and Thrombosis 1991;ll:509-516)

Abstract-One of the genetic features of the Sardinian population is the high prevalence of hemoglobin disorders. It has been estimated that 13% to 33% of Sardinians carry a mutant allele of the ␣-globin gene (␣-thalassemia trait) and that 6% to 17% are ␤-thalassemia carriers. In this population, a single mutation of ␤-globin gene (Q39X, ␤ 0 39) accounts for Ͼ95% of ␤-thalassemia cases. Because previous studies have shown that Sardinian ␤-thalassemia carriers have lower total and low density lipoprotein (LDL) cholesterol than noncarriers, we wondered whether this LDL-lowering effect of the ␤-thalassemia trait was also present in subjects with familial hypercholesterolemia (FH). In a group of 63 Sardinian patients with the clinical diagnosis of FH, we identified 21 unrelated probands carrying 7 different mutations of the LDL receptor gene, 2 already known (313ϩ1 gϾa and C95R) and 5 not previously reported (D118N, C255W, A378T, T413R, and Fs572). The 313ϩ1 gϾa and Fs572 mutations were found in several families. In cluster Fs572, the plasma LDL cholesterol level was 5.76Ϯ1.08 mmol/L in subjects with ␤ 0 -thalassemia trait and 8.25Ϯ1.66 mmol/L in subjects without this trait (PϽ0.001). This LDL-lowering effect was confirmed in an FH heterozygote of the same cluster who had ␤ 0 -thalassemia major and whose LDL cholesterol level was below the 50th percentile of the distribution in the normal Sardinian population. The hypocholesterolemic effect of ␤ 0 -thalassemia trait emerged also when we pooled the data from all FH subjects with and without ␤ 0 -thalassemia trait, regardless of the type of mutation in the LDL receptor gene. The LDL-lowering effect of ␤ 0 -thalassemia may be related to (1) the mild erythroid hyperplasia, which would increase the LDL removal by the bone marrow, and (2) the chronic activation of the monocyte-macrophage system, causing an increased secretion of some cytokines (interleukin-1, interleukin-6, and tumor necrosis factor-␣) known to affect the hepatic secretion and the receptor-mediated removal of apolipoprotein B-containing lipoproteins. The observation that our FH subjects with ␤ 0 -thalassemia trait (compared with noncarriers) have an increase of blood reticulocytes (40%) and plasma levels of interleukin-6 (ϩ60%) supports these hypotheses. The lifelong LDL-lowering effect of ␤ 0 -thalassemia trait might slow the development and progression of coronary atherosclerosis in FH.