Subtyping Severe Hypercholesterolemia by Genetic Determinant to Stratify Risk of Coronary Artery Disease.

Background: Severe hypercholesterolemia, defined as LDL (low-density lipoprotein) cholesterol (LDL-C) measurement ≥190 mg/dL, is associated with increased risk for coronary artery disease (CAD). Causes of severe hypercholesterolemia include monogenic familial hypercholesterolemia, polygenic hypercholesterolemia, elevated lipoprotein(a) [Lp(a)] hypercholesteremia, polygenic hypercholesterolemia with elevated Lp(a) (two-hit), or nongenetic hypercholesterolemia. The added value of using a genetics approach to stratifying risk of incident CAD among those with severe hypercholesterolemia versus using LDL-C levels alone for risk stratification is not known.

Four missense genetic variants in are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes: A genetic association study in Europeans.

Aim: Rare genetic variants in the gene encoding the main albumin-transporter in the proximal tubule of the kidneys have previously been associated with microalbuminuria and higher urine albumin levels, also in diabetes. Sequencing studies in isolated proteinuria suggest that these variants might not affect kidney function, despite proteinuria. However, the relation of these missense variants to the estimated glomerular filtration rate (eGFR) is largely unexplored.

The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification.

Purpose: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified.

Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel.

Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing.

High Diabetes Distress Among Ethnic Minorities Is Not Explained by Metabolic, Cardiovascular, or Lifestyle Factors: Findings From the Dutch Diabetes Pearl Cohort.

Objective: Diabetes distress among patients from ethnic minorities is still poorly understood. We investigated the association between ethnicity and diabetes distress among ethnic minority groups of people with type 2 diabetes in the Netherlands, focusing on the possible effects of glycemic control, lifestyle factors, cardiovascular risk factors, and diabetes complications.

Research Design And Methods: Cross-sectional data from the Dutch Diabetes Pearl cohort included people with type 2 diabetes from primary, secondary, and tertiary diabetes care programs.

Cardiovascular risk in patients with familial hypercholesterolemia using optimal lipid-lowering therapy.

Background: Despite lipid-lowering therapy (LLT), some patients with familial hypercholesterolemia (FH) still develop cardiovascular events. Data about the quantification and factors contributing to this residual risk are lacking.

Objective: This study assessed how many patients with FH developed a cardiovascular event despite LLT and which factors contribute to this risk.

Group cognitive behavioural therapy and weight regain after diet in type 2 diabetes: results from the randomised controlled POWER trial.

Aims/hypothesis: Weight-loss programmes for adults with type 2 diabetes are less effective in the long term owing to regain of weight. Our aim was to determine the 2 year effectiveness of a cognitive behavioural group therapy (group-CBT) programme in weight maintenance after diet-induced weight loss in overweight and obese adults with type 2 diabetes, using a randomised, parallel, non-blinded, pragmatic study design.

Methods: We included 158 obese adults (median BMI 36.

Proprotein convertase subtilisin/kexin 9 inhibition in patients with familial hypercholesterolemia: Initial clinical experience.

Background: Despite optimal lipid-lowering therapy, a minority of patients with familial hypercholesterolemia (FH) reach low-density lipoprotein cholesterol (LDL-c) target goals. In randomized trials, proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors led to impressive LDL-c reductions and a favorable safety profile. However, data about the efficacy and safety outside clinical trials are not available yet.

Oxidized LDL, Gamma-Glutamyltransferase and Adverse Outcomes in Older Adults.

Objectives: Gamma-glutamyltransferase (GGT) is a biomarker of liver disease and oxidative stress which was associated with all-cause and cardiovascular (CV) mortality in the general population and in patients with high risk conditions. This study aims at assessing whether oxLDL modifies the relationship between GGT, all-cause, and CV mortality in elderly individuals from the general population.

Design: Observational longitudinal study.

Low-density lipoprotein receptor-negative compound heterozygous familial hypercholesterolemia: Two lifetime journeys of lipid-lowering therapy.

We present the case history of 2 patients with low-density lipoprotein receptor-negative compound heterozygous familial hypercholesterolemia who did not receive lipoprotein apheresis. We describe the subsequent effect of all lipid-lowering medications during their life course including resins, statins, ezetimibe, nicotinic acid/laropiprant, mipomersen, and lomitapide. These cases tell the story of siblings affected with this rare disease, who are free of symptoms but still are at a very high cardiovascular disease risk, and their treatment from childhood.

Low-density lipoprotein receptor mutational analysis in diagnosis of familial hypercholesterolemia.

Purpose Of Review: To present up to date evidence on the pathogenicity of low-density lipoprotein receptor (LDLR) variants and to propose a strategy that is suitable for implementation in the clinical work-up of familial hypercholesterolaemia.

Recent Findings: More than 1800 variants have been described in the LDLR gene of patients with a clinical diagnosis of familial hypercholesterolaemia; however, less than 15% have functional evidence of pathogenicity.

Summary: The spectrum of variants in the LDLR identified in patients with clinical familial hypercholesterolaemia is increasing as novel variants are still being reported.

Serum Levels of Apolipoproteins and Incident Type 2 Diabetes: A Prospective Cohort Study.

Objective: We aimed to investigate the role of serum levels of various apolipoproteins on the risk for type 2 diabetes (T2D).

Research Design And Methods: We used data from 971 individuals from the prospective population-based Rotterdam Study. We studied the association of HDL cholesterol (HDL-C), apoA1, apoCIII, apoD, and apoE as well as the ratios of apolipoproteins with apoA1 with the risk of T2D.

Carotid artery plaques and intima medial thickness in familial hypercholesteraemic patients on long-term statin therapy: A case control study.

Background And Aims: Statins reduce subclinical atherosclerosis and premature atherosclerotic cardiovascular disease (ASCVD) in patients with familial hypercholesterolemia (FH). However, some FH patients still develop ASCVD despite statin therapy. We compared subclinical atherosclerosis assessed by carotid plaque presence and intima media thickness (C-IMT), in long-term statin-treated FH patients and healthy controls.

ADAMTS13 activity as a novel risk factor for incident type 2 diabetes mellitus: a population-based cohort study.

Aims/hypothesis: ADAMTS13 is a protease that breaks down von Willebrand factor (VWF) multimers into smaller, less active particles. VWF has been associated with an increased risk of incident type 2 diabetes mellitus. Here, we determine whether ADAMTS13 activity and VWF antigen are associated with incident diabetes.

Levels of the soluble LDL receptor-relative LR11 decrease in overweight individuals with type 2 diabetes upon diet-induced weight loss.

Background And Aims: Cardiovascular disease (CVD) is a major complication in patients with type 2 diabetes (T2D), especially in those with obesity. Plasma soluble low density lipoprotein receptor-relative with 11 ligand-binding repeats (sLR11) plays a role in the development of atherosclerosis and has been linked to the metabolism of triglyceride-rich lipoproteins, adiposity, and vascular complications in T2D. We aimed to determine the effect of diet-induced weight loss on plasma sLR11 levels in overweight and obese individuals with T2D.

Genomic prediction of coronary heart disease.

Aims: Genetics plays an important role in coronary heart disease (CHD) but the clinical utility of genomic risk scores (GRSs) relative to clinical risk scores, such as the Framingham Risk Score (FRS), is unclear. Our aim was to construct and externally validate a CHD GRS, in terms of lifetime CHD risk and relative to traditional clinical risk scores.

Methods And Results: We generated a GRS of 49 310 SNPs based on a CARDIoGRAMplusC4D Consortium meta-analysis of CHD, then independently tested it using five prospective population cohorts (three FINRISK cohorts, combined n = 12 676, 757 incident CHD events; two Framingham Heart Study cohorts (FHS), combined n = 3406, 587 incident CHD events).

The Relationship of Metabolic Syndrome Traits with Beta-Cell Function and Insulin Sensitivity by Oral Minimal Model Assessment in South Asian and European Families Residing in the Netherlands.

Background. There are different metabolic syndrome traits among patients with different ethnicities. Methods.

Predictors of Diet-Induced Weight Loss in Overweight Adults with Type 2 Diabetes.

Aims: A very low calorie diet improves the metabolic regulation of obesity related type 2 diabetes, but not for all patients, which leads to frustration in patients and professionals alike. The aim of this study was to develop a prediction model of diet-induced weight loss in type 2 diabetes.

Methods: 192 patients with type 2 diabetes and BMI>27 kg/m2 from the outpatient diabetes clinic of the Erasmus Medical Center underwent an 8-week very low calorie diet.

Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel.

Familial hypercholesterolaemia is common in individuals who had a myocardial infarction at a young age. As many as one in 200 people could have heterozygous familial hypercholesterolaemia, and up to one in 300 000 individuals could be homozygous. The phenotypes of heterozygous and homozygous familial hypercholesterolaemia overlap considerably; the response to treatment is also heterogeneous.

Familial hypercholesterolaemia: cholesterol efflux and coronary disease.

Background: Coronary heart disease (CHD) risk inversely associates with levels of high-density lipoprotein cholesterol (HDL-C). The protective effect of HDL is thought to depend on its functionality, such as its ability to induce cholesterol efflux.

Materials And Methods: We compared plasma cholesterol efflux capacity between male familial hypercholesterolaemia (FH) patients with and without CHD relative to their non-FH brothers, and examined HDL constituents including sphingosine-1-phosphate (S1P) and its carrier apolipoprotein M (apoM).

The clinical value of metabolic syndrome and risks of cardiometabolic events and mortality in the elderly: the Rotterdam study.

Background: To evaluate the clinical value of metabolic syndrome based on different definitions [American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI), International Diabetes Federation (IDF) and European Group for the Study of Insulin Resistance (EGIR)] in middle-aged and elderly populations.

Methods: We studied 8643 participants from the Rotterdam study (1990-2012; mean age 62.7; 57.

Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.

Background: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.