Detection of familial hypercholesterolemia by assaying functional low-density-lipoprotein receptors on lymphocytes

In familial hypercholesterolemia, structural and functional abnormalities of the receptor for low-density lipoprotein (LDL) lead to hypercholesterolemia and premature atherosclerosis. We have developed a simplified method to identify LDL-receptor defects in peripheral-blood lymphocytes. When lymphocytes are cultured in lipoprotein-depleted medium and endogenous sterol biosynthesis is suppressed with mevinolin, mitogen-stimulated proliferation of lymphocytes is dependent on an exogenous source of cholesterol. Whereas a small concentration of supplemental LDL cholesterol (3 to 4 micrograms per milliliter) permits a maximal response in normal lymphocytes, even high concentrations (10 to 50 micrograms per milliliter) are unable to support the proliferation of lymphocytes from patients with homozygous familial hypercholesterolemia. Thus, functional LDL receptors are necessary to allow lymphocyte proliferation in these cultures. The response of lymphocytes from patients with hyperlipidemia not caused by defective LDL receptors was like that of normal cells. In contrast, the response of lymphocytes from patients with heterozygous familial hypercholesterolemia was intermediate between that of homozygotes and that of normal or hyperlipidemic controls. Our method can therefore be used to identify persons who are heterozygous for abnormalities of LDL receptors.