β-thalassemia is a modifying factor of the clinical expression of familial hypercholesterolemia

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, bthalassemia 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 b-globin chain of hemoglobin (beta-thalassemia). Plasma LDL-C in FH heterozygotes carrying the b-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.