β-Thalassemia Is a Modifying Factor of the Clinical Expression of Familial Hypercholesterolemia

Abstract

Familial hypercholesterolemia (FH) is a codominant disorder due to a variety of mutations of the low-density lipoprotein (LDL) receptor gene that result in an elevation of plasma LDL-cholesterol (LDL-C). Plasma levels of LDL-C show large interindividual variation even in subjects carrying the same mutation of the LDL receptor gene. This variability may be due to genetic factors (modifier genes). Several surveys indicate that the overall contribution of common polymorphisms of modifier genes (such as the genes encoding apolipoproteins E and B) to this variability is less than 10%. In contrast, beta-thalassemia has a profound LDL-lowering effect. This was documented in FH patients identified on the island of Sardinia, in Italy, where 12% of the inhabitants are carriers of beta-thalassemia due to a single mutation (Q39X) of the beta-globin gene that abolishes the synthesis of beta-globin chain of hemoglobin (beta(o)-thalassemia). Plasma LDL-C in FH heterozygotes carrying the beta(o)-thalassemia trait is 25% lower than in noncarriers, regardless of the LDL receptor gene mutation. It is likely that this effect is due to two main mechanisms: (1) increased uptake of LDL by the bone marrow to provide cholesterol for the increased proliferation of erythroid progenitor cells and (2) increased production of inflammatory cytokines that reduce the hepatic secretion and increase the catabolism of LDL. In view of its LDL-C-lowering effect, beta-thalassemia trait may protect FH heterozygotes against premature coronary atherosclerosis.

A complex phenotype in a child with familial HDL deficiency due to a novel frameshift mutation in APOA1 gene (apoA-I Guastalla )

“…Moreover, the LDL lowering effect associated with the b-thalassemia trait may be also related to the activation of the monocyte/macrophage system in spleen, liver, and bone marrow with the generation of several inflammatory cytokines, which at least in vitro in HepG2 cells, increase LDLR gene expression and reduce the assembly of apoB-containing lipoproteins. 38 In addition, a recent meta-analysis of 8 case-control studies (involving 9479 individuals) showed that the b-thalassemia trait was associated with a reduced risk of arterial cardiovascular and cerebrovascular events in male patients (odds ratio 0.39; confidence interval 0.24-0.62). 39 In agreement with the aforementioned findings, the LDL-C level was ,25 th percentile in proband's mother and ,15 th percentile in proband's grandfather with respect to the distribution of LDL-C level in gender-and age-matched normal individuals of the Italian population.…”

Hypocholesterolemia in chronic anemias with increased erythropoietic activity

“…Presently, the clinical implications of this anemia-associated hypocholestrolemia are unknown. It has been suggested that, in b-thalassemia, hypocholesterolemia is a modifying factor underlying the clinical expression of familial hypercholesterolemia [12]. Some previous data suggest that the incidence of coronary artery disease is lower in patients with b-thalassemia compared with controls [9].…”

“…The pathophysiology of the hypocholesterolemia in these settings remains obscure, although several mechanisms have been proposed: plasma dilution due to anemia, increased cholesterol requirement associated with erythroid hyperplasia, macrophage system activation with cytokine release, increased cholesterol uptake by the reticuloendotial system, and liver injury secondary to iron overload [2,3]. Few small uncontrolled studies have also suggested a lower incidence of coronary artery disease in anemic patients with b-thalassemia and hereditary spherocytosis [9][10][11][12].…”

Premature Atherosclerosis in Non-Transfusion-Dependent β-Thalassemia Intermedia

“…The present plasma cholesterol pattern is not confined to β-TI but extends to all β-thalassemic syndromes [11,12]. We hypothesize a promotion of vascular damage in a milieu of hemostatic abnormalities, oxidative stress, and immunomodulation, each of which has been constantly demonstrated among thalassemic patients, whether regularly transfused or not [1,5,6,9,12].…”