Apolipoprotein Isoform E4 Does Not Increase Coronary Heart Disease Risk in Carriers of Low-Density Lipoprotein Receptor Mutations

Abstract

Background-In humans, the E4 allele of the apolipoprotein E gene is associated with increased coronary heart disease risk. Surprisingly, in rodents, apolipoprotein E4 only accelerates the atherosclerotic process when transgenic for the human low-density lipoprotein receptor (LDLR) protein. We therefore investigated whether the LDLR locus interacted with the apolipoprotein E gene genotype on coronary heart disease risk in patients clinically diagnosed with familial hypercholesterolemia with and without LDLR mutation. We investigated whether the presence of an LDLR mutation diminishing LDLR function was protective in E4/E4 carriers. Methods and Results-In a cohort of 2400 patients clinically diagnosed with familial hypercholesterolemia, we found an LDLR gene mutation in 1383 patients, whereas in 1013 patients, such mutation was not present. In 92 patients homozygous for the apolipoprotein E4, the presence of an LDLR mutation conferred lower coronary heart disease risk (hazard ratio, 0.16; 95% CI, 0.05-0.58; Pϭ0.005). Mirroring these results, the apolipoprotein E4/E4 genotype was also associated with lower coronary heart disease risk in patients with familial hypercholesterolemia with an LDLR mutation (hazard ratio, 0.26; hazard ratio, 0.08 -0.80; Pϭ0.02). Conclusions-LDLR function is key to the detrimental effects of apolipoprotein E4 in humans. Kinetic studies in humans are now required to study the consequences of our observation for prevention of both coronary heart disease and Alzheimer disease. (Circ Cardiovasc Genet. 2011;4:655-660.)Key Words: apolipoprotein E Ⅲ coronary heart disease Ⅲ familial hypercholesterolemia C omplications of atherosclerotic vascular disease are the most common causes of death and morbidity in the Western world with coronary heart disease (CHD) as its most prominent manifestation. 1 Hereditary predisposition plays an important role in the pathobiology of atherosclerosis. One of the genes best known for its association with CHD risk is the 1 coding for the low-density lipoprotein receptor (LDLR) protein. Mutations in this gene cause an autosomal-dominant disorder called familial hypercholesterolemia (FH), which is characterized by severe hypercholesterolemia and premature CHD. 2 Another important gene known to influence CHD risk is apolipoprotein E (APOE). 3 Mice completely lacking the ApoE protein are severely hypercholesterolemic and develop extensive atherosclerotic lesions, a process that is accelerated when they are fed a high-fat diet. 4,5 Homozygous deficiency of the APOE gene in humans is extremely rare and is also characterized by atherogenic lipid abnormalities and premature CHD. 6,7 Clinical Perspective on p 660In humans, 3 main haplotypes of the APOE gene have been identified: APOE2, APOE3, and APOE4. The encoded ApoE2, ApoE3, and ApoE4 proteins differ in their amino acid sequences at positions 112 and 158. Although these differences are not located in the LDLR binding domain, affinity to the LDLR differs between genotypes: ApoE2 has the lowest affinity for the LDLR, where...

Liver X receptors at the intersection of lipid metabolism and atherogenesis

“…Several receptor-dependent pathways clear circulating cholesterol. LDL receptors bind APOB- and APOE-containing apolipoproteins and internalize them via receptor-mediated endocytosis 1, 110 . Cholesterol is also cleared by through selective uptake from HDL particles by SCARB1 111 and by the internalization of HDL particles 112 .…”

Genetic Susceptibility to Atherosclerosis

“…Of these variants, apoE3 is the most frequent (>60%) in all populations studied [19]. The role of apoE in plasma lipid metabolism has been studied intensively [20, 21]. The polymorphism has functional effects on lipoprotein metabolism mediated through the hepatic binding, uptake, and catabolism of chylomicrons, chylomicron remnants, very low-density lipoprotein (VLDL), and high-density lipoprotein subspecies [22].…”

Elevated Levels of LDL-C are Associated With ApoE4 but Not With the rs688 Polymorphism in the LDLR Gene

“…The authors suggest further studies to establish the biological basis of their findings. 28 In summary, our results suggest that women carrying the ApoE4 isoform present high levels of LDL-C and/or TG, have a higher risk of developing atherosclerosis, and consequently CHD. And the SNP rs688 in the LDLR gene does not confer greater susceptibility of atherogenic risk in the women studied.…”