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[Background and aims] Lipoprotein(a) [Lp(a)] concentration in heterozygous familial hypercholesterolemia (heFH) is not well established. Whether the genetic defect responsible for heFH plays a role in Lp(a) concentration is unknown. We aimed to compare Lp(a) in controls from a healthy population, in genetically diagnosed heFH and mutation-negative hypercholesterolemia subjects, and to assess the influence on Lp(a) of the genetic defect responsible for heFH., [Methods] We conducted a cross-sectional study, performed in a lipid clinic in Spain. We studied adults with suspected heFH and a genetic study of FH genes (LDLR, APOB, APOE and PCSK9) and controls from de Aragon Workers’ Health Study. HeFH patients from the Dyslipidemia Registry of the Spanish Atherosclerosis Society (SEA) were used as validation cohort., [Results] Adjusted geometric means (95% confidence interval) of Lp(a) in controls (n = 1059), heFH (n = 500), and mutation-negative subjects (n = 860) were 14.9 mg/dL (13.6, 16.4), 21.9 mg/dL (18.1, 25.6) and 37.4 mg/dL (33.3, 42.1), p < 0.001 in all comparisons. Among heFH subjects, APOB-dependent FH showed the highest Lp(a), 36.5 mg/dL (22.0, 60.8), followed by LDLR-dependent FH, 21.7 mg/dL (17.9, 26.4). These differences were also observed in heFH from the SEA cohort. The number of plasminogen-like kringle IV type−2 repeats of LPA, the hypercholesterolemia polygenic score or LDLc concentration did not explain these differences. In LDLR-dependent FH, Lp(a) levels were not different depending on the affected protein domain., [Conclusions] Lp(a) is elevated in mutation-negative subjects and in heFH. The concentration of Lp(a) in heFH varies in relation to the responsible gene. Higher Lp(a) in heFH is not explained by their higher LDLc., This study was supported by grants from the Spanish Ministry of Economy and Competitiveness PI 18/01777, PI 19/00694 and CIBERCV; and Gobierno de Aragón B-14. These projects are co-financed by Instituto de Salud Carlos III and the European Regional Development Fund (ERDF) of the European Union ‘‘A way to make Europe”.

Background Familial hypercholesterolemia (FH) may arise from deleterious monogenic variants in FH‐causing genes as well as from a polygenic cause. We evaluated the relationships between monogenic FH and polygenic hypercholesterolemia in influencing the long‐term response to therapy and the risk of atherosclerosis. Methods and Results A cohort of 370 patients with clinically diagnosed FH were screened for monogenic mutations and a low‐density lipoprotein‐rising genetic risk score >0.69 to identify polygenic cause. Medical records were reviewed to estimate the response to lipid‐lowering therapies and the occurrence of major atherosclerotic cardiovascular events during a median follow‐up of 31.0 months. A subgroup of patients (n=119) also underwent coronary computed tomographic angiography for the evaluation of coronary artery calcium score and severity of coronary stenosis as compared with 135 controls. Two hundred nine (56.5%) patients with hypercholesterolemia were classified as monogenic (FH/M+), 89 (24.1%) as polygenic, and 72 (19.5%) genetically undefined (FH/M−). The response to lipid‐lowering therapy was poorest in monogenic, whereas it was comparable in patients with polygenic hypercholesterolemia and genetically undetermined. Mean coronary artery calcium score and the prevalence of coronary artery calcium >100 units were significantly higher in FH/M+ as compared with both FH/M− and controls. Finally, after adjustments for confounders, we observed a 5‐fold higher risk of incident major atherosclerotic cardiovascular events in FH/M+ (hazard ratio, 4.8; 95% CI, 1.06–21.36; P adj =0.041). Conclusions Monogenic cause of FH is associated with lower response to conventional cholesterol‐lowering therapies as well as with increased burden of coronary atherosclerosis and risk of atherosclerotic‐related events. Genetic testing for hypercholesterolemia is helpful in providing important prognostic information.

Hypercholesterolemia is a major cause of atherosclerosis development and premature cardiovascular disease (CVD). It leads to inflammation, which further accelerates atherosclerosis progression. Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated serum LDL-c from birth, due to a disease-causing variant in one of the causative genes (LDLR, APOB, PCSK9). In polygenic hypercholesterolemia (PH), the disease-causing genetic variant is absent; it is likely the cumulative result of multiple single nucleotide polymorphisms in LDL metabolism-related genes and other factors, such as lifestyle and environment. In high risk groups, such as patients with FH, an effective primary prevention of CVD must begin in childhood. High-sensitivity C-reactive protein (hsCRP) and carotid intima media thickness (cIMT) are two potential minimally invasive correlates of inflammation and subclinical atherosclerosis progression. hsCRP and cIMT have been shown to be significantly increased in patients with FH and PH relative to healthy controls, with some studies yielding conflicting results. In this review, we aim to summarize current knowledge and recent findings regarding the applicability of hsCRP and cIMT as markers of low-grade inflammation and subclinical atherosclerosis, focusing especially on children and adolescents with hypercholesterolemia.

Background: The monogenic defect in familial hypercholesterolemia (FH) is detected in &sim, 40% of cases. The majority of mutation-negative patients have a polygenic cause of high LDL-cholesterol (LDL-C). We sought to investigate whether the underlying monogenic or polygenic defect is associated with the response to rosuvastatin. Methods: FH Individuals were tested for mutations in LDLR and APOB genes. A previously established LDL-C-specific polygenic risk score (PRS) was used to examine the possibility of polygenic hypercholesterolemia in mutation-negative patients. All of the patients received rosuvastatin and they were followed for 8 &plusmn, 2 months. A propensity score analysis was performed to evaluate the variables associated with the response to treatment. Results: Monogenic subjects had higher mean (&plusmn, SD) baseline LDL-C when compared to polygenic (7.6 &plusmn, 1.5 mmol/L vs. 6.2 &plusmn, 1.2 mmol/L, p &lt, 0.001). Adjusted model showed a lower percentage of change in LDL-C after rosuvastatin treatment in monogenic patients vs. polygenic subjects (45.9% vs. 55.4%, p &lt, 0.001). The probability of achieving LDL-C targets in monogenic FH was lower than in polygenic subjects (0.075 vs. 0.245, p = 0.004). Polygenic patients were more likely to achieve LDL-C goals, as compared to those monogenic (OR 3.28, 95% CI: 1.23&ndash, 8.72). Conclusion: Our findings indicate an essentially higher responsiveness to rosuvastatin in FH patients with a polygenic cause, as compared to those carrying monogenic mutations.

Background: Diet is considered the cornerstone of lipid management in hyperlipidemic children but evidence to demonstrate the effects of nutrient benefits on the lipid profile is limited. Aim: The aim of this study is to evaluate the impact of the Mediterranean diet on low-density lipoprotein (LDL-C) and non-high density lipoprotein (HDL-C) decrease in primary hyperlipidemia affected children and in the achievement of therapeutical target levels. Methods: A retrospective cohort study was used, recruiting n = 223 children (10.05 ± 3.26 mean age years) with familial hypercholesterolemia (FH) (n = 61, 27%) and polygenic hypercholesterolemia (PH) (n =162, 73%). Secondary hyperlipidemias were excluded. Based on LDL-C and non-HDL-C decrease, participants were divided into two groups, named the Responder Group and Non-Responder Group. Participants and their families underwent dietary education by an expert nutritionist and were asked to fill in a weekly diary to be delivered at visits. Dietary indications were in line with daily caloric requirement, daily food quality and quantity intakes typical of the Mediterranean diet. These include carbohydrates, extra virgin olive oil, yoghurt and milk derivatives, fish and vegetable proteins, fresh seasonal vegetables and fresh fruits. Nuts or almonds were also recommended. The advice to limit intakes of meat, in particular red meat, and caution against junk food and sugar added food and beverages was provided. At medical visits, carried out at baseline (T0) and 6 months later (T1), children underwent anthropometric measurements and blood collection. Standard kits and methods were applied for lipid analysis. Statistical methods were performed by SAS version 9.4 (SAS Institute, Cary, NC, USA). Signed informed consent was given by parents according to the Declaration of Helsinki and the study was approved by the Local Committee. Results: The Responder Group (n = 156/223, 70%) included 45 FH and 111 PH children, while the Non-Responder Group (n = 67/223, 30%) included 16 FH and 51 PH children. The Responder Group showed total cholesterol (TC), LDL-C and non-HDL-C median percentage decreases of 9.45, 13.51 and 10.90, respectively. These statistically significant changes (p ≤ 0.0001) were similar in the FH and PH subgroups but just PH subjects reached the LDL-C and non-HDL-C target, which fell below 130 mg/dL and 145 mg/dL, respectively. Saturated fatty acids (SFAs) were the main dietary parameter that distinguished between the Responder Group and the Non-Responder Group (p = 0.014). Positive correlations were found at T1 between dietary total lipids, SFAs and cholesterol with serum LDL-C, non-HDL-C and TC variations. These latter serum parameters had an inverse correlation with dietary carbohydrate at T1. Among macronutrients, SFAs were finally demonstrated to be the predictor of serum lipids variation at T1. Conclusions: The dietary intervention with a Mediterranean diet in children with primary hyperlipidemia significantly improves the lipid profile both in FH and PH subgroups and allows target levels of LDL-C and non-HDL-C in PH subjects to be reached. Responsiveness benefits should be primarily attributed to the reduction in SFAs, but changes in dietary lipids, cholesterol and carbohydrate intake may also play a role. In contrast, the Non-Responder Group showed a worsening of lipid profile regarding the unchanged diet.

Background and aims Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia. Methods FH mutation testing and genotypes of six LDL-C-associated single nucleotide polymorphisms (SNPs) were determined using routine methods. Those with a detected mutation (monogenic) and mutation-negative patients with LDL-C SNP score in the top two quartiles (polygenic) were recruited. Carotid intima media thickness (IMT) was measured by B-mode ultrasound and the coronary artery calcium (CAC) score was performed in three lipid clinics in the UK and the Netherlands. Results 86 patients (56 monogenic FH, 30 polygenic) with carotid IMT measurement, and 166 patients (124 monogenic, 42 polygenic) with CAC score measurement were examined. After adjustment for age and gender, the mean of all the carotid IMT measurements and CAC scores were significantly greater in the monogenic than the polygenic patients [carotid IMT mean (95% CI): 0.74 mm (0.7–0.79) vs. 0.66 mm (0.61–0.72), p = 0.038 and CAC score mean (95%): 24.5 (14.4–41.8) vs. 2.65 (0.94–7.44), p = 0.0004]. Conclusions In patients with a diagnosis of FH, those with a monogenic cause have a higher severity of carotid and coronary preclinical atherosclerosis than those with a polygenic aetiology., Highlights • Patients with clinical FH but no detectable mutation are likely to have a polygenic cause for their raised LDL-C. • Preclinical atherosclerosis was measured in both groups, matched for lipid levels. • Carotid Intima Media Thickness was greater in monogenic vs polygenic patients. • Coronary artery calcification score was greater in monogenic vs polygenic patients. • Monogenic FH patients have greater preclinical atherosclerosis than those with a polygenic aetiology.

Purpose of the Review Identification of loci and common single-nucleotide polymorphisms (SNPs) that have modest effects on plasma lipids have been used to confirm or refute the causal role of lipid traits in the development of coronary heart disease (CHD), and as tools to identify individuals with polygenic hypercholesterolemia. Recent Findings Several groups have reported on the use of SNP scores in distinguishing individuals with a clinical diagnosis of familial hypercholesterolemia (FH) with a monogenic or polygenic etiology. We review evidence that those with monogenic FH have worse prognosis and discuss the possible mechanisms for this and their management. Summary Individuals with a clinical phenotype of FH and a monogenic cause are at greater risk of CHD than those where no causative mutation can be found. The patients with polygenic hypercholesterolemia would not require elaborate cascade screening or secondary care input for their management.

BACKGROUND: Autosomal dominant hypercholesterolemia (ADH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes, and it is estimated to be greatly underdiagnosed. The most cost-effective strategy for increasing ADH diagnosis is a cascade screening from mutation-positive pro bands. OBJECTIVE: The objective of this study was to evaluate the results from 2008 to 2016 of ADH genetic analysis performed in our clinical laboratory, serving most lipid units of Catalonia, a Spanish region with approximately 7.5 million inhabitants. METHODS: After the application of the Dutch Lipid Clinic Network (DLCN) clinical diagnostic score for ADH, this information and blood or saliva from 23 different lipid clinic units were investigated in our laboratory. DNA was screened for mutations in LDLR, APOB, and PCSK9, using the DNA-array LIPOchip, the next-generation sequencing SEQPRO LIPO RS platform, and multiplex ligation dependent probe amplification (MLPA). The Simon Broome Register Group (SBRG) criteria was calculated and analyzed for comparative purposes. RESULTS: A total of 967 unrelated samples were analyzed. From this, 158 pathogenic variants were detected in 356 patients. The main components of the DLCN criteria associated with the presence of mutation were plasma LDL cholesterol (LDLc), age, and the presence of tendinous xanthomata. The contribution of family history to the diagnosis was lower than in other studies. DLCN and SBRG were similarly useful for predicting the presence of mutation. CONCLUSION: In a real clinical practice, multicenter setting in Catalonia, the percentage of positive genetic diagnosis in patients potentially affected by ADH was 38.6%. The DLCN showed a relatively low capacity to predict mutation detection but a higher one for ruling out mutation. (C) 2018 National Lipid Association. All rights reserved.

Platelet-activating factor-acetylhydrolase (PAF-AH) is a lipoprotein-associated phospholipase A 2 capable of hydrolyzing platelet-activating factor (PAF) and oxidatively modified phospholipids. We studied the plasma- and lipo- protein-associated PAF-AH activity in patients with primary hypercholesterolemia. Thirty-eight unrelated patients with heterozygous familial hypercholesterolemia (HeteroFH), five patients with homozygous FH (HomoFH), and 33 pa- tients with primary non-FH hypercholesterolemia (NonFH) participated in the study. In all patient groups the plasma PAF-AH activity was significantly elevated compared with 33 normolipidemic controls, the HomoFH having the highest and the NonFH patients showing the lowest enzyme activity. Gradient ultracentrifugation studies showed that this increase is not only due to the elevation in the plasma LDL but also to the increase in the PAF-AH activity associated with each LDL subfraction, being more profound in the small-dense LDL-5. Unlike LDL, no difference in the HDL-associated PAF-AH activity was observed among all groups. Consequently, an al- tered distribution of enzyme activity among apolipoprotein B (apoB)- and apolipoprotein A-I (apoA-I)-containing lipopro- teins is observed in hypercholesterolemic patients, resulting in a significant decrease in the ratio of the HDL-associated PAF-AH to the total plasma enzyme activity compared with controls. This reduction is proportional to the increase of the plasma LDL-cholesterol (LDL-C) levels and consequently to the severity of the hypercholesterolemia. Thus, the ratio of HDL-associated PAF-AH-total plasma enzyme activity may be useful as a potential marker of atherogenicity in subjects with primary hypercholesterolemia. —Tsimihodimos, V., S-A. P. Karabina, A. P. Tambaki, E. Bairaktari, G. Miltiadous, J. A. Goudevenos, M. A. Cariolou, M. J. Chapman, A. D. Tsele- pis, and M. Elisaf. Altered distribution of platelet-activating factor-acetylhydrolase activity between LDL and HDL as a function of the severity of hypercholesterolemia. J. Lipid Res. 2002. 43: 256-263.

WOS: 000294257800004, PubMed: 21804277, Background Increased levels of selectins, adhesion molecules, hs-CRP and homocysteine are considered important as indicators of atherosclerosis. There is a significant amount of evidence that high LDL-C levels are a risk factor for coronary artery disease, whereas the relevance of isolated triglycerides is controversial. The present study aims to compare the levels of homocysteine, hs-CRP, E-selectin, sP-selectin, VCAM-1, ICAM-1 in patients with isolated hypertriglyceridemia and polygenic hypercholesterolemia. Methods The following three groups were formed: polygenic hypercholesterolemia group (n=30), isolated hypertriglyceridemia group (n=30) and control group (n=30). These three groups were matched in terms of BMI, waist circumference and gender. Plasma high sensitive CRP, homocysteine, sVCAM-1, sICAM-1, sP-selectin, sE-Selectin levels of patients in these three groups were measured. Results In the present study, mean values for sE-selectin, sVCAM-1 and sICAM-1 in the polygenic hypercholesterolemia group were significantly higher than in the other two groups (p0.05), where as the hs-CRP value was significantly higher in patients with isolated hypertriglyceridemia compared to the control group (p=0.001). Conclusion The increase of adhesion molecules, homocysteine and hs-CRP in polygenic hypercholesterolemia subjects compared to the isolated hypertriglyceridemia group reflects their high cardiovascular risk.

Objective— Achilles tendon (AT) xanthomas, specific for familial hypercholesterolemia (FH), may be clinically undetectable. We assessed the usefulness of AT sonography in the diagnosis of FH. Methods and Results— Sonographic AT characteristics were evaluated in 127 subjects with FH (81 genetically ascertained), 84 familial combined hyperlipidemia, 79 polygenic hypercholesterolemia, and 88 normolipidemic controls. Abnormal echostructure (sonographic xanthoma) was noted only in FH. AT thickness was higher ( P r =0.345; P r =−0.265, P =0.015). Thickness thresholds for the diagnosis of FH with specificity >80%, as were derived from receiver operating curves, were 5.3 and 5.7 mm in men < and >45 years, and 4.8 and 4.9 mm in women < and >50 years, respectively. In FH mutation carriers, sonographic findings increased the clinical diagnosis of xanthomas from 35 (43%) to 55 (68%). Using thresholds in validation sets of 70 genetically identified FH and 54 dyslipidemic non-FH correctly classified 80% and 88%, respectively. Conclusion— Sonographic AT characteristics are normal in non-FH dyslipidemias. Identification of suspected FH by ultrasound using sex- and age-specific AT thickness thresholds is recommended.

The genetic background of polygenic hypercholesterolemia was studied in hypercholesterolemic children consuming a diet identical to control individuals with low cholesterol concentrations. Significantly higher frequencies of "disadvantage" alleles, usually combined with a higher LDL cholesterol, were found in hypercholesterolemic individuals when polymorphisms in apolipoprotein E, apolipoprotein B--XbaI and LDL receptor--PvuII were studied.

In a randomized, cross-over feeding trial involv- ing 10 men with polygenic hypercholesterolemia, a control, Mediterranean-type cholesterol-lowering diet, and a diet of similar composition in which walnuts replaced � 35% of en- ergy from unsaturated fat, were given for 6 weeks each. Compared with the control diet, the walnut diet reduced serum total and LDL cholesterol by 4.2% ( P � 0.176), and 6.0% ( P � 0.087), respectively. No changes were observed in HDL cholesterol, triglycerides, and apolipoprotein A-I levels or in the relative proportion of protein, triglycerides, phospholipids, and cholesteryl esters in LDL particles. The apolipoprotein B level declined in parallel with LDL choles- terol (6.0% reduction). Whole LDL, particularly the triglyc- eride fraction, was enriched in polyunsaturated fatty acids from walnuts (linoleic and � -linolenic acids). In comparison with LDL obtained during the control diet, LDL obtained during the walnut diet showed a 50% increase in association rates to the LDL receptor in human hepatoma HepG2 cells. LDL uptake by HepG2 cells was correlated with � -linolenic acid content of the triglyceride plus cholesteryl ester frac- tions of LDL particles ( r 2 � 0.42, P � 0.05). Changes in the quantity and quality of LDL lipid fatty acids after a walnut- enriched diet facilitate receptor-mediated LDL clearance and may contribute to the cholesterol-lowering effect of walnut consumption. —Munoz, S., M. Merlos, D. Zambon, C. Rodriguez, J. Sabate, E. Ros, and J. C. Laguna. Walnut- enriched diet increases the association of LDL from hyper- cholesterolemic men with human HepG2 cells. J. Lipid Res. 2001. 42: 2069-2076.

Background and aims Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia.