title: Influence of beta(0)-thalassemia on the phenotypic expression of heterozygous familial hypercholesterolemia : a study of patients with familial hypercholesterolemia from Sardinia.
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 alpha-globin gene (alpha-thalassemia trait) and that 6% to 17% are beta-thalassemia carriers. In this population, a single mutation of beta-globin gene (Q39X, beta(0) 39) accounts for >95% of beta-thalassemia cases. Because previous studies have shown that Sardinian beta-thalassemia carriers have lower total and low density lipoprotein (LDL) cholesterol than noncarriers, we wondered whether this LDL-lowering effect of the beta-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 beta(0)-thalassemia trait and 8.25+/-1.66 mmol/L in subjects without this trait (P<0.001). This LDL-lowering effect was confirmed in an FH heterozygote of the same cluster who had beta(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 beta(0)-thalassemia trait emerged also when we pooled the data from all FH subjects with and without beta(0)-thalassemia trait, regardless of the type of mutation in the LDL receptor gene. The LDL-lowering effect of beta(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-alpha) known to affect the hepatic secretion and the receptor-mediated removal of apolipoprotein B-containing lipoproteins. The observation that our FH subjects with beta(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 beta(0)-thalassemia trait might slow the development and progression of coronary atherosclerosis in FH.
authors.affiliation: Institute of Clinical Biochemistry, University of Sassari, Sassari, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Deiana
authors.forename: R
authors.initials: R
authors.lastname: Garuti
authors.forename: G M
authors.initials: GM
authors.lastname: Pes
authors.forename: C
authors.initials: C
authors.lastname: Carru
authors.forename: A
authors.initials: A
authors.lastname: Errigo
authors.forename: M
authors.initials: M
authors.lastname: Rolleri
authors.forename: L
authors.initials: L
authors.lastname: Pisciotta
authors.forename: P
authors.initials: P
authors.lastname: Masturzo
authors.forename: A
authors.initials: A
authors.lastname: Cantafora
authors.forename: S
authors.initials: S
authors.lastname: Calandra
authors.forename: S
authors.initials: S
authors.lastname: Bertolini
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D016207:Cytokines / Q000097:blood; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005914:Globins / Q000235:genetics; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000150:complications* / Q000235:genetics*; D007558:Italy; D008077:Lipoproteins, LDL / Q000097:blood; D008262:Macrophage Activation; D008297:Male; D009154:Mutation; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics; D017086:beta-Thalassemia / Q000097:blood / Q000150:complications* / Q000235:genetics*
chemical_list: D016207:Cytokines; D017931:DNA Primers; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D005914:Globins