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.