JLR Patient-Oriented and Epidemiological Research
Lipid and metabolic syndrome traits in coronary artery disease: a Mendelian randomization study
Mendelian randomization (MR) of lipid traits in CAD has provided evidence for causal associations of LDL-C and TGs in CAD, but many lipid trait genetic variants have pleiotropic effects on other cardiovascular risk factors that may bias MR associations. The goal of this study was to evaluate pleiotropic effects of lipid trait genetic variants and to account for these effects in MR of lipid traits in CAD. We performed multivariable MR using inverse variance-weighted and MR-Egger methods in large (n ≥ 300,000) GWAS datasets.Progression of chronic kidney disease in familial LCAT deficiency: a follow-up of the Italian cohort
Familial LCAT deficiency (FLD) is a rare genetic disorder of HDL metabolism, caused by loss-of-function mutations in the LCAT gene and characterized by a variety of symptoms including corneal opacities and kidney failure. Renal disease represents the leading cause of morbidity and mortality in FLD cases. However, the prognosis is not known and the rate of deterioration of kidney function is variable and unpredictable from patient to patient. In this article, we present data from a follow-up of the large Italian cohort of FLD patients, who have been followed for an average of 12 years.A genome-wide search for gene-by-obesity interaction loci of dyslipidemia in Koreans shows diverse genetic risk alleles
Dyslipidemia is a well-established risk factor for CVD. Studies suggest that similar fat accumulation in a given population might result in different levels of dyslipidemia risk among individuals; for example, despite similar or leaner body composition compared with Caucasians, Asians of Korean descent experience a higher prevalence of dyslipidemia. These variations imply a possible role of gene-obesity interactions on lipid profiles. Genome-wide association studies have identified more than 500 loci regulating plasma lipids, but the interaction structure between genes and obesity traits remains unclear.Plasma apoM and S1P levels are inversely associated with mortality in African Americans with type 2 diabetes mellitus
apoM is a minor HDL apolipoprotein and carrier for sphingosine-1-phosphate (S1P). HDL apoM and S1P concentrations are inversely associated with atherosclerosis progression in rodents. We evaluated associations between plasma concentrations of S1P, plasma concentrations of apoM, and HDL apoM levels with prevalent subclinical atherosclerosis and mortality in the African American-Diabetes Heart Study participants (N = 545). Associations between plasma S1P, plasma apoM, and HDL apoM with subclinical atherosclerosis and mortality were assessed using multivariate parametric, nonparametric, and Cox proportional hazards models.Cholesterol efflux capacity, HDL cholesterol, and risk of coronary heart disease: a nested case-control study in men
The capacity of HDLs to accept cholesterol effluxing from macrophages has been proposed as a new biomarker of HDLs' anti-atherogenic function. Whether cholesterol efflux capacity (CEC) is independent of HDL cholesterol (HDL-C) as a biomarker for coronary heart disease (CHD) risk in a generally healthy primary-prevention population remains unanswered. Therefore, in this nested case-control study, we simultaneously assessed CEC (using J774 cells) and plasma HDL-C levels as predictors of CHD in healthy middle-aged and older men not receiving treatment affecting blood lipid concentrations.Does pregnancy alter life-course lipid trajectories? Evidence from the HUNT Study in Norway
We examined the association between pregnancy and life-course lipid trajectories. Linked data from the Nord-Trøndelag Health Study and the Medical Birth Registry of Norway yielded 19,987 parous and 1,625 nulliparous women. Using mixed-effects spline models, we estimated differences in nonfasting lipid levels from before to after first birth in parous women and between parous and nulliparous women. HDL cholesterol (HDL-C) dropped by −4.2 mg/dl (95% CI: −5.0, −3.3) from before to after first birth in adjusted models, a 7% change, and the total cholesterol (TC) to HDL-C ratio increased by 0.18 (95% CI: 0.11, 0.25), with no change in non-HDL-C or triglycerides.Scavenger receptor BI promotes cytoplasmic accumulation of lipoproteins in clear-cell renal cell carcinoma
Clear-cell renal cell carcinomas (ccRCCs) are characterized by inactivation of the von Hippel-Lindau (VHL) gene and intracellular lipid accumulation by unknown pathomechanisms. The immunochemical analysis of 356 RCCs revealed high abundance of apoA-I and apoB, as well as scavenger receptor BI (SR-BI) in the ccRCC subtype. Given the characteristic loss of VHL function in ccRCC, we used VHL-defective and VHL-proficient cells to study the potential influence of VHL on lipoprotein uptake. VHL-defective patient-derived ccRCC cells and cell lines (786O and RCC4) showed enhanced uptake as well as less resecretion and degradation of radio-iodinated HDL and LDL (125I-HDL and 125I-LDL, respectively) compared with the VHL-proficient cells.Genome-wide association study identifies novel recessive genetic variants for high TGs in an Arab population
Abnormal blood lipid levels are influenced by genetic and lifestyle/dietary factors. Although many genetic variants associated with blood lipid traits have been identified in Europeans, similar data in Middle Eastern populations are limited. We performed a genome-wide association study with Arab individuals (discovery cohort: 1,353; replication cohort: 1,176) from Kuwait to identify possible associations of genetic variants with high lipid levels. We used Illumina HumanOmniExpress BeadChip and candidate SNP genotyping in the discovery and replication phases, respectively.Cholesterol efflux capacity does not associate with coronary calcium, plaque vulnerability, and telomere length in healthy octogenarians
Several studies have revealed that traditional risk factors are less effective in predicting CVD risk in the elderly, suggesting the need to identify new biomarkers. Here, we evaluated the association between serum cholesterol efflux capacity (CEC), an atheroprotective property of HDL recently identified as a novel marker of CVD risk, and atherosclerotic burden in a cohort of very old, healthy individuals. Serum CEC values were not significantly correlated either with calcium score or with markers of vulnerable plaque, such as positive remodeling, hypodensity, spotty calcification, or napking-ring sign.Obesity is associated with an altered HDL subspecies profile among adolescents with metabolic disease
We aimed to determine the risk factors associated with the depletion of large HDL particles and enrichment of small HDL particles observed in adolescents with T2D. Four groups of adolescents were recruited: 1) lean insulin-sensitive (L-IS), normal BMI and no insulin resistance; 2) lean insulin-resistant (L-IR), normal BMI but insulin resistance (fasting insulin levels ≥ 25 mU/ml and homeostatic model assessment of insulin resistance ≥ 6); 3) obese insulin-sensitive (O-IS), BMI ≥ 95th percentile and no insulin resistance; and 4) obese insulin-resistant (O-IR), BMI ≥ 95th percentile and insulin resistance.Associations of anthropometry and lifestyle factors with HDL subspecies according to apolipoprotein C-III
The presence of apoC-III on HDL impairs HDL's inverse association with coronary heart disease (CHD). Little is known about modifiable factors explaining variation in HDL subspecies defined according to apoC-III. The aim was to investigate cross-sectional associations of anthropometry and lifestyle with HDL subspecies in 3,631 participants from the Diet, Cancer, and Health study originally selected for a case-cohort study (36% women; age 50–65 years) who were all free of CHD. Greater adiposity and less activity were associated with higher HDL containing apoC-III and lower HDL lacking apoC-III.Depletion in LpA-I:A-II particles enhances HDL-mediated endothelial protection in familial LCAT deficiency
The aim of this study was to evaluate the vasoprotective effects of HDL isolated from carriers of LCAT deficiency, which are characterized by a selective depletion of LpA-I:A-II particles and predominance of preβ migrating HDL. HDLs were isolated from LCAT-deficient carriers and tested in vitro for their capacity to promote NO production and to inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in cultured endothelial cells. HDLs from carriers were more effective than control HDLs in promoting eNOS activation with a gene-dose-dependent effect (PTrend = 0.048).Associations of genetic variants for adult lipid levels with lipid levels in children. The Generation R Study
Lipid concentrations are heritable traits. Recently, the number of known genetic loci associated with lipid levels in adults increased from 95 to 157. The effects of these 157 loci have not been tested in children. Considering that lipid levels track from childhood to adulthood, we studied to determine whether these variants already affected lipid concentrations in a large group of 2,645 children with a median age of 6.0 years (95% range 5.7–7.3 years) from the population-based Generation R Study.The relationship between non-HDL cholesterol and macrophage phenotypes in human adipose tissue
Data from experimental animal models and in vitro studies suggest that both hyperlipoproteinemia and obesity predispose to development of proinflammatory pathways of macrophages within adipose tissue. The aim of this study was to analyze whether non-HDL cholesterol concentration in healthy living kidney donors (LKDs) is related to the number and phenotype of proinflammatory macrophages in visceral and subcutaneous adipose tissue. Adipose tissue samples were collected by cleansing the kidney grafts of LKDs obtained peroperatively.Associations between intensive diabetes therapy and NMR-determined lipoprotein subclass profiles in type 1 diabetes
Our objective is to define differences in circulating lipoprotein subclasses between intensive versus conventional management of type 1 diabetes during the randomization phase of the Diabetes Control and Complications Trial (DCCT). NMR-determined lipoprotein subclass profiles (NMR-LSPs), which estimate molar subclass concentrations and mean particle diameters, were determined in 1,294 DCCT subjects after a median of 5 years (interquartile range: 4–6 years) of randomization to intensive or conventional diabetes management.Characterization of circulating APOL1 protein complexes in African Americans
APOL1 gene renal-risk variants are associated with nephropathy and CVD in African Americans; however, little is known about the circulating APOL1 variant proteins which reportedly bind to HDL. We examined whether APOL1 G1 and G2 renal-risk variant serum concentrations or lipoprotein distributions differed from nonrisk G0 APOL1 in African Americans without nephropathy. Serum APOL1 protein concentrations were similar regardless of APOL1 genotype. In addition, serum APOL1 protein was bound to protein complexes in two nonoverlapping peaks, herein referred to as APOL1 complex A (12.2 nm diameter) and complex B (20.0 nm diameter).HDL-apolipoprotein A-I exchange is independently associated with cholesterol efflux capacity
HDL is the primary mediator of cholesterol mobilization from the periphery to the liver via reverse cholesterol transport (RCT). A critical first step in this process is the uptake of cholesterol from lipid-loaded macrophages by HDL, a function of HDL inversely associated with prevalent and incident cardiovascular disease. We hypothesized that the dynamic ability of HDL to undergo remodeling and exchange of apoA-I is an important and potentially rate-limiting aspect of RCT. In this study, we investigated the relationship between HDL-apoA-I exchange (HAE) and serum HDL cholesterol (HDL-C) efflux capacity.Protective associations of HDL with blood-brain barrier injury in multiple sclerosis patients
The purpose of this work was to investigate the associations of serum cholesterol and apolipoproteins with measures of blood-brain barrier (BBB) permeability and CNS inflammation following the first clinical demyelinating event. This study included 154 patients [67% female; age, 29.5 ± 8.2 years (mean ± SD)] enrolled in a multi-center study of interferon β1-a treatment following the first demyelinating event. Blood and cerebrospinal fluid (CSF) were obtained at screening prior to treatment. A comprehensive serum lipid profile and multiple surrogate markers of BBB breakdown and CNS immune activity were obtained.Targeted next-generation sequencing to diagnose disorders of HDL cholesterol
A low level of HDL cholesterol (HDL-C) is a common clinical scenario and an important marker for increased cardiovascular risk. Many patients with very low or very high HDL-C have a rare mutation in one of several genes, but identification of the molecular abnormality in patients with extreme HDL-C is rarely performed in clinical practice. We investigated the accuracy and diagnostic yield of a targeted next-generation sequencing (NGS) assay for extreme levels of HDL-C. We developed a targeted NGS panel to capture the exons, intron/exon boundaries, and untranslated regions of 26 genes with highly penetrant effects on plasma lipid levels.Genetic meta-analysis of 15,901 African Americans identifies variation in EXOC3L1 is associated with HDL concentration
Meta-analyses of European populations has successfully identified genetic variants in over 150 loci associated with lipid levels, but results from additional ethnicities remain limited. Previously, we reported two novel lipid loci identified in a sample of 7,657 African Americans using a gene-centric array including 50,000 SNPs in 2,100 candidate genes. Initial discovery and follow-up of signals with P < 10−5 in additional African American samples confirmed CD36 and ICAM1. Using an additional 8,244 African American female samples from the Women's Health Initiative SNP Health Association Resource genome-wide association study dataset, we further examined the previous meta-analyses results by attempting to replicate 20 additional putative lipid signals with P < 10−4.Levels of atherogenic lipoproteins are unexpectedly reduced in interstitial fluid from type 2 diabetes patients
At a given level of serum cholesterol, patients with T2D have an increased risk of developing atherosclerosis compared with nondiabetic subjects. We hypothesized that T2D patients have an increased interstitial fluid (IF)-to-serum gradient ratio for LDL, due to leakage over the vascular wall. Therefore, lipoprotein profiles in serum and IF from 35 T2D patients and 35 healthy controls were assayed using fast performance liquid chromatography. The IF-to-serum gradients for VLDL and LDL cholesterol, as well as for apoB, were clearly reduced in T2D patients compared with healthy controls.
