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Background: Autosomal dominant hypercholesterolemia (ADH) is due to deleterious variants in LDLR , APOB , or PCSK9 genes. Double heterozygote for these genes induces a more severe phenotype. More recently, a new causative variant of heterozygous ADH was identified in APOE . Here we study the phenotype of 21 adult patients, double heterozygotes for rare LDLR and rare APOE variants ( LDLR+APOE ) in a national wide French cohort. Methods: LDLR , APOB , PCSK9 , and APOE genes were sequenced in 5743 probands addressed for ADH genotyping. The lipid profile and occurrence of premature atherosclerotic cardiovascular diseases were compared between the LDLR+APOE carriers (n=21) and the carriers of the same LDLR causative variants alone (n=22). Results: The prevalence of LDLR+APOE carriers in this French ADH cohort is 0.4%. Overall, LDL (low-density lipoprotein)-cholesterol concentrations were 23% higher in LDLR+APOE patients than in LDLR patients (9.14±2.51 versus 7.43±1.59 mmol/L, P=0 .0221). When only deleterious or probably deleterious variants were considered, the LDL-cholesterol concentrations were 46% higher in LDLR+APOE carriers than in LDLR carriers (10.83±3.45 versus 7.43±1.59 mmol/L, P=0 .0270). Two patients exhibited a homozygous familial hypercholesterolemia phenotype (LDL-cholesterol >13 mmol/L). Premature atherosclerotic cardiovascular disease was more common in LDLR+APOE patients than in LDLR carriers (70% versus 30%, P=0 .026). Conclusions: Although an incomplete penetrance should be taken into account for APOE variant classification, these results suggest an additive effect of deleterious APOE variants on ADH phenotype highlighting the relevance of APOE sequencing.

Objective— Low high-density lipoprotein (HDL) cholesterol levels are frequently observed in familial hypercholesterolemia (FH) and might be associated with functional alterations of HDL particles that may influence their efficaciousness in the reverse cholesterol transport pathway. Methods and Results— We evaluated key steps of the reverse cholesterol transport, ie, cellular free cholesterol efflux, cholesteryl ester transfer protein-mediated cholesteryl ester (CE) transfer from HDL to apolipoprotein B–containing lipoproteins, and hepatic HDL-CE uptake, in patients displaying FH (n=12) and in healthy normolipidemic control subjects (n=12). Large HDL2 particles isolated from FH patients displayed a reduced capacity to mediate free cholesterol efflux via both scavenger receptor-BI– and ABCG1–dependent pathways. A significant inverse relationship between scavenger receptor-BI–dependent HDL2 efflux capacity and carotid intima-media thickness ( r =−0.473; P =0.0186), as well as between ABCG1-dependent HDL2 efflux capacity and carotid intima-media thickness ( r =−0.485; P =0.0212), was detected. We also observed an elevated cholesteryl ester transfer protein-mediated CE transfer from HDL2 and HDL3 particles to low-density lipoprotein and a reduced capacity of HDL particles to deliver CEs to the liver. Conclusion— We demonstrated that the centripetal movement of cholesterol from peripheral tissues, including the vessel wall, to feces is defective in FH, thereby emphasizing its atherogenicity.

The advent of the HMG-CoA reductase inhibitors, or statins, in the 1980’s as highly efficacious agents for the lowering of low-density lipoprotein-cholesterol (LDL-C) revolutionized treatment of hypercholesterolemia, a long established risk factor for premature coronary heart disease. Indeed, a recent prospective meta-analysis of data from more than 90 000 participants in 14 randomized clinical trials revealed that a statin-mediated reduction of 1 mmol/L (40 mg/dL) in LDL-C that is sustained for 5 years may produce a proportional reduction in major vascular events of some 23%.1 Greater reductions in LDL-C, which may be attained with intensive statin therapy as exemplified in the recent Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22), Treating to New Targets (TNT), and Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trials involving use of atorvastatin (80 mg/d), produce larger reductions in vascular disease risk.2–4 Importantly, risk reductions are proportional to the absolute reduction in LDL-C1, and moreover clinical benefit may be apparent with intensive statin treatment as early as 30 days after initiation in acute coronary syndrome patients, with significant decrement in cardiovascular morbi-mortality.5 See page 2560 Statins not only exhibit a remarkably high benefit to risk ratio, but are equally characterized by a safety profile with excellent tolerance.6,7 Nonetheless, statins may exert toxic effects on skeletal muscle which are generally referred to as myopathy, and whose overall incidence is typically

Objective— Maintenance of cholesterol homeostasis in human macrophages is essential to prevent foam cell formation. We evaluated the relative contribution of the ABCA1 and ABCG1 transporters to cholesterol efflux from human macrophages, and of the capacity of LXR agonists to reduce foam cell formation by stimulating export of cellular cholesterol. Methods and Results— ABCG1 mRNA levels were strongly increased in acLDL-loaded THP-1 macrophages and in HMDM on stimulation with LXR agonists. However, silencing of ABCG1 expression using ABCG1-specific siRNA indicated that ABCG1 was not essential for cholesterol efflux to HDL in cholesterol-loaded human macrophages stimulated with LXR agonists. Indeed, ABCA1 was solely responsible for the stimulation of cholesterol efflux to HDL on LXR activation, as this effect was abolished in HMDM from Tangier patients. Furthermore, depletion of cellular ATP indicated that the LXR-induced export of cholesterol was an ATP-dependent transport mechanism in human macrophages. Finally, use of an anti–Cla-1 blocking antibody identified the Cla-1 receptor as a key component in cholesterol efflux to HDL from cholesterol-loaded human macrophages. Conclusion— Our data indicate that stimulation of cholesterol efflux to HDL by LXR agonists in human foam cells involves an ATP-dependent transport mechanism mediated by ABCA1 that it appears to be independent of ABCG1 expression.

Background— Prospective cohort studies have revealed that plasma γ-glutamyltransferase (GGT) activity exhibits a positive association with coronary artery disease. GGT which is equally elevated in metabolic syndrome (MS), is the major regulator of circulating concentrations of thiol compounds derived from glutathione (GSH) cleavage, ie, cysteine and cysteinyl glycine. We compared the circulating thiol profile in a cohort of patients displaying atherogenic dyslipidemia with and without MS. Methods and Results— This cross-sectional study involved 1131 dyslipidemic patients in primary prevention of whom 26% presented with MS. GGT activity and plasma cysteinyl-glycine and cysteine concentrations were higher in MS patients; by contrast, levels of GSH were significantly lower ( P P for trend −6 ). Conclusion— Dyslipidemic patients exhibiting MS are characterized by elevated GGT activity which is associated with perturbed metabolism of thiol compounds.