Twelve Variants Polygenic Score for Low-Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations

: Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease-causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low-density lipoprotein cholesterol (LDL-C)-raising variants (polygenic LDL-C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH-mutation positive (women, 54.75%; mean age, 42.47±15.00 years) and 644 patients who were FH-mutation negative (women, 54.21%; mean age, 49.73±13.54 years) were evaluated. Patients who were FH-mutation negative had lower mean levels of pretreatment LDL-C than patients who were FH-mutation positive (217.14±55.49 versus 270.52±68.59 mg/dL, P<0.0001). The mean value (±SD) of the polygenic LDL-C risk score was 1.00 (±0.18) in patients who were FH-mutation negative and 0.94 (±0.20) in patients who were FH-mutation positive (P<0.0001). In the receiver operating characteristic analysis, the area under the curve for recognizing subjects characterized by polygenic hypercholesterolemia was 0.59 (95% CI, 0.56-0.62), with sensitivity and specificity being 78% and 36%, respectively, at 0.905 as a cutoff value. Higher mean polygenic LDL-C risk score levels were observed among patients who were FH-mutation negative having pretreatment LDL-C levels in the range of 150 to 350 mg/dL (150-249 mg/dL: 1.01 versus 0.91, P<0.0001; 250-349 mg/dL: 1.02 versus 0.95, P=0.0001). A positive correlation between polygenic LDL-C risk score and pretreatment LDL-C levels was observed among patients with FH independently of the presence of causative mutations. Conclusions This analysis confirms the role of polymorphisms in modulating LDL-C levels, even in patients with genetically confirmed FH. More data are needed to support the use of the polygenic score in routine clinical practice

I farmaci che riducono la mortalit\ue0: gli ipolipemizzanti

Cardiovascular disease (CVD) is the leading cause of death in Italy and in the 28 countries of the European Union. Low-density lipoprotein cholesterol (LDL-C) is a key CVD risk factor. Results from the randomized intervention clinical trials with lipid-lowering agents strongly suggest that the reduction of fatal and non-fatal CVD events is associated with the absolute LDL-C reduction, in mg/dl or mmol/L, regardless of the lipid-lowering agent studied. Statins, by decreasing cholesterol synthesis in the liver, are associated with a large LDL-C reduction and with robust and convincing evidence of a significant reduction of all-cause, CVD and coronary heart disease (CHD) mortality. An LDL-C reduction by 39 mg/dl (1 mmol/L) on statin therapy is associated with a decrease by 10% (p<0.0001) in all-cause mortality, by 20% (p<0.0001) in CHD deaths and by 24% (p<0.0001) in major cardiovascular events. These results were often observed in secondary CVD prevention patients (4S, HPS and LIPID trials), independently of patients\u2019 gender and age, in patients on primary CVD prevention at high CV risk and in patients with type two diabetes. In patients with diabetes a 39 mg/dl (1 mmol/L) LDL-C reduction is associated with a decrease by 9% (p=0.02) in all-cause mortality, by 12% (p=0.03) and 13% (p=0.008) in deaths due to CHD and CVD causes respectively, and by 21% (p<0.0001) in major cardiovascular events. Data on CVD and CHD mortality regarding ezetimibe, fibrates and PCSK9 inhibitors are not nearly as robust as those with statin therapy: a significant reduction with these lipid-lowering agents has been observed in combined clinical endpoints including fatal and non-fatal CVD events while no significant reduction in all-cause, CVD or CHD mortality has been reported. This lack of positive results on CVD and CHD mortality should be interpreted in the light of remarkable changes in the background therapy to prevent CVD events seen in patients enrolled in the more recent trials where aggressive antihypertensive, antiplatelet and lipid-lowering therapy are common enrollment criteria for both control and active treatment groups

Relevance of hepatic lipase to the metabolism of triacylglycerol-rich lipoproteins

HL (hepatic lipase) is a glycoprotein that is synthesized and secreted by the liver, and which binds to heparan sulphate proteoglycans on the surface of sinusoidal endothelial cells and on the external surface of parenchymal cells in the space of Disse. HL catalyses the hydrolysis of triacylglycerols and phospholipids in different lipoproteins, contributing to the remodelling of VLDL (very-low-density lipoprotein) remnants, as well as IDL, LDL and HDL (intermediate-, low- and high-density lipoprotein respectively). HL deficiency in humans is associated with diminished conversion of VLDL remnants into IDL and a near-complete absence of IDL-to-LDL conversion. Remnant lipoproteins and IDL are major determinants of coronary artery disease risk, and accumulation of these lipoproteins in the presence of low HL activity might lead to increased atherosclerosis. In addition to and independently of its lipolytic activity, HL participates as a ligand in promoting the hepatic uptake of remnants and IDL particles, and the latter may represent an additional mechanism linking low HL levels to plasma accumulation of these atherogenic lipoproteins. On the other hand, high HL activity may also result in an increased atherosclerotic risk by promoting the formation of atherogenic small, dense LDL particles. Finally, HL is also synthesized by human macrophages, suggesting that, at the arterial wall site, HL may also contribute locally to promote atherosclerosis by enhancing the formation and retention in the subendothelial space of the arterial wall of VLDL remnants, IDL and small, dense LDL. In conclusion, by interfering with the metabolism of apolipoprotein B100-containing lipoproteins, HL may have pro- as well as anti-atherogenic effects. The anti- or pro-atherogenic role of HL is likely to be modulated by the concurrent presence of other lipid abnormalities (i.e. LDL-cholesterol levels), as well as by the genetic regulation of other enzymes involved in lipoprotein metabolism