© 2000 American Heart Association, Inc.
Thrombosis |
Influence of ß0-Thalassemia on the Phenotypic Expression of Heterozygous Familial Hypercholesterolemia
A Study of Patients With Familial Hypercholesterolemia From Sardinia
From the Institute of Clinical Biochemistry (L.D., G.M.P., C.C., A.E.), University of Sassari, Sassari, Italy; the Department of Biomedical Sciences (R.G., S.C.), University of Modena, Modena, Italy; the Department of Internal Medicine (M.R., L.P., P.M., S.B.), University of Genoa, Genoa, Italy; and the National Institute of Health (A.C.), Rome, Italy.
Correspondence to Stefano Bertolini, Department of Internal Medicine, V.le Benedetto XV, 6, I-16132 Genova, Italy. E-mail stefbert{at}unige.it
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 ß-thalassemia
carriers. In this population, a single mutation of ß-globin gene
(Q39X, ß0 39) accounts for >95% of ß-thalassemia
cases. Because previous studies have shown that Sardinian
ß-thalassemia carriers have lower total and low density lipoprotein
(LDL) cholesterol than noncarriers, we wondered whether
this LDL-lowering effect of the ß-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 ß0-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 ß0-thalassemia major and whose LDL
cholesterol level was below the 50th percentile of the
distribution in the normal Sardinian population. The
hypocholesterolemic effect of
ß0-thalassemia trait emerged also when we pooled the data
from all FH subjects with and without ß0-thalassemia
trait, regardless of the type of mutation in the LDL receptor gene. The
LDL-lowering effect of ß0-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 ß0-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
ß0-thalassemia trait might slow the development and
progression of coronary atherosclerosis in
FH.
Key Words: familial hypercholesterolemia • low density lipoprotein receptor gene mutations • ß-thalassemia • gene-gene interaction
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