Influence of β0-Thalassemia on the Phenotypic Expression of Heterozygous Familial Hypercholesterolemia

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 α-globin gene (α-thalassemia trait) and that 6% to 17% are β-thalassemia carriers. In this population, a single mutation of β-globin gene (Q39X, β 0 39) accounts for >95% of β-thalassemia cases. Because previous studies have shown that Sardinian β-thalassemia carriers have lower total and low density lipoprotein (LDL) cholesterol than noncarriers, we wondered whether this LDL-lowering effect of the β-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 (313+1 g>a and C95R) and 5 not previously reported (D118N, C255W, A378T, T413R, and Fs572). The 313+1 g>a and Fs572 mutations were found in several families. In cluster Fs572, the plasma LDL cholesterol level was 5.76±1.08 mmol/L in subjects with β 0 -thalassemia trait and 8.25±1.66 mmol/L in subjects without this trait ( P 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 β 0 -thalassemia trait emerged also when we pooled the data from all FH subjects with and without β 0 -thalassemia trait, regardless of the type of mutation in the LDL receptor gene. The LDL-lowering effect of β 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-α) known to affect the hepatic secretion and the receptor-mediated removal of apolipoprotein B–containing lipoproteins. The observation that our FH subjects with β 0 -thalassemia trait (compared with noncarriers) have an increase of blood reticulocytes (40%) and plasma levels of interleukin-6 (+60%) supports these hypotheses. The lifelong LDL-lowering effect of β 0 -thalassemia trait might slow the development and progression of coronary atherosclerosis in FH.