Variation In Cholesterol Levels Research Articles

The Cycle study: a prospective study on cholesterol levels during the menstrual cycle

Abstract Background Previous studies showed fluctuating lipid levels during the menstrual cycle in healthy women with normal cholesterol (nChol). Cycle-related variations in lipid levels in women with familial hypercholesterolemia (FH) have not been studied, while these might have important consequences for lipid management. Purpose To investigate menstrual cycle-related fluctuations in lipid levels in women with FH compared to those with nChol. Methods In the Netherlands and Norway, 20 women with clinical/genetic FH and 63 healthy women with nChol were included - details are presented in the figures. Participants had to have a regular cycle between 21-35 days, while pregnant women, and those using hormone-based contraceptives without hormone free interval (HFI) were excluded. Lipid levels were measured in the follicular (visit 1), ovulation (visit 2), and luteal (visit 3) phases. In women using oral contraceptives (OC) measurements were taken during day 12-14 of the pill period (visit 1) and during day 5-7 of the HFI (visit 2). Results Mean (sd) age of the included subjects was 33 (9) years, BMI 23.9 (4) kg/m2, and cycle duration 28 (2) days. These characteristics were similar in FH and nChol. Women with nChol showed slight, although statistically significant, cycle-related variations in cholesterol levels (mean maximum variation total Chol 0.53, LDL-Chol 0.39 and HDL-Chol 0.22 mmol/L; figure 1). FH women who did not receive statin therapy for various reasons showed largest mean variations (total Chol 0.80, LDL-Chol 0.59 and HDL-Chol 0.23 mmol/L), with the highest lipid levels during the ovulation phase. The women with OC had an increase in total- and LDL-cholesterol (groups combined: mean difference 0.55 and 0.51 mmol/L, respectively) between the two visits (n=9) (figure 2). Conclusions In women with untreated FH and normal cholesterol with a regular menstrual cycle, total- and HDL-cholesterol were highest at ovulation. These menstrual fluctuations were absent in women with FH who used statins. Women with OC showed an increase in total- and LDL-cholesterol from the contraceptive pill period to the HFI. Even though in most women the absolute variation in lipid levels during the menstrual cycle and OC are modest, the moment of measurement can be of clinical value in particular in women with untreated high lipid levels. In these women, it is recommended to measure lipid levels at a fixed time of the menstrual cycle.Figure 1Figure 2

Lipid variability in patients with diabetes mellitus

Diabetic dyslipidemia is characterized by hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), elevated low-density lipoprotein cholesterol (LDL-C), and the predominance of small dense LDL particles caused by insulin resistance in patients with type 2 diabetes mellitus (DM) or insulin deficiency in patients with type 1 DM. Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease in individuals with DM, and lowering lipid levels can reduce the associated morbidity and mortality. The current guidelines for dyslipidemia management recommend an LDL-C goal lower than 55 to 100 mg/dL, depending on the underlying risk factors. However, greater visit-to-visit variability in cholesterol levels might be an independent predictor of major adverse cardiovascular events, high incidence of atrial fibrillation, poor renal outcomes, and cognitive dysfunction in patients with DM. This review focuses on the clinical implications of lipid variability in patients with DM.

Effect of cholesterol variability on the incidence of cataract, dementia, and osteoporosis: A study using a common data model.

The effects of cholesterol variability on cataracts, dementia, and osteoporosis remain controversial. Using a common data model, we investigated the effects of variations in cholesterol levels on the development of cataracts, dementia, and osteoporosis. Patients who received statin therapy between 2011 and 2020 and those with 3 or more tests for total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels were included. The patients were divided into those with a coefficient of variation (CV) of TC higher than the mean (high-CV group) and those with a lower CV of TC (low-CV group). Moreover, 1:1 propensity score matching was conducted based on demographic variables. Cataract, dementia, or osteoporosis was defined as having a diagnostic, drug, or surgical code based on the cohort definition. Of the 12,882 patients, cataracts, dementia, and osteoporosis were developed in 525 (4.1%), 198 (1.5%), and 438 (3.4%) patients, respectively. The stratified Cox proportional hazards model showed that the incidences of cataracts and osteoporosis were 1.38 and 1.45 times greater in the high-CV group than in the low-CV group, respectively. Our study revealed that TC variability is associated with developing cataracts and osteoporosis.

The Biochemical Assessments of Cellular Oxidant - Antioxidant Status and Lipid Profile for Some of COVID-19 Vaccines (Pfizer, AstraZeneca and Sinopharm) in Vaccinated People of Wasit Province in Iraq

Background: Coronaviruses (SARS-CoV-2) cause COVID-19 pandemic in March, 2020, after Chinese scientists published the genome of the virus vaccine manufacturer produced several COVID-19 vaccines that aimed to induce a humoral and cellular immune response to prevent the fatality and harm caused by COVID-19. Existing study aimed to evaluate the biochemical efficiency of some of COVID-19 vaccines (Pfizer, AstraZeneca and Sinopharm) in vaccinated people of Wasit Province in Iraq by lipid profile estimation, Human SOD1 (Superoxide Dismutase 1, Soluble) and Human Malondialdehyde (MDA).Methods: The current study sample included (55) individuals whom vaccinated with two shots of one of the three vaccines (Pfizer, AstraZeneca and Sinopharm) whom did not suffer from chronic health problems, and a control group of (35) unvaccinated individuals of both genders. Their age ranges from 18-45 years, they were divided into two age ranges (18-31 and 32-45 years) and their vaccination history was confirmed according to a special form. The blood samples were collected from fasting vaccinated individuals 2-4 weeks post the second dose of COVID-19 vaccine for the purpose of conducting lipid profile, SOD and MDA.RESULTS: The data of serous endogenous oxidative–antioxidants balance showed a variation in the concentrations of malondialdehyde (MDA), its significant increase (P≤0.05) was observed in those vaccinated with the Pfizer vaccine for the first age range (31-18 years) and its insignificant decrease (P> 0.05) in the two Sinopharm and AstraZeneca vaccines in both age ranges and both genders comparing to the control group. Besides, the findings of estimating the serum level of enzyme Superoxide dismutase (SOD) was not significantly different (P> 0.05) between the vaccinated people of this study for all three vaccines and the control group for both age ranges and both genders. Additionally, the serum lipid profile levels (TG, LDL, HDL and VLDL) of the vaccinated individuals were not significantly changed (P>0.05) compared to the control group (unvaccinated individuals) except for the cleared variation in cholesterol level among the first age range for both genders compared to the control group.Conclusion: the findings of the present study showed that all the three targeted vaccines in the study (Pfizer, AstraZeneca and Sinopharm) have shown a high efficacy and safely on body oxidation balance and heart in terms of the biochemical assessment (MDA, SOD and lipid profile) of the healthy vaccinated participants.

Lipid Variability and Diabetes Mellitus

Diabetic dyslipidemia is characterized by hypertriglyceridemia, low HDL (high-density lipoprotein)-cholesterol, elevated LDL (low-density lipoprotein)-cholesterol, and predominance of small dense LDL particles caused by insulin resistance in type 2 diabetes or insulin deficiency in type 1 diabetes. Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease in diabetes, and lowering lipid levels can reduce its morbidity and mortality. Current guidelines for dyslipidemia management recommend that the LDL-C goal be lower than 55~100 mg/dL depending on the underlying risk factors. However, higher visit-to-visit variability in cholesterol levels might be an independent predictor of major adverse cardiovascular events and poor renal outcomes in diabetes. In this review, we focused on clinical implications of lipid variability in diabetes.

Abstract 13554: High-Throughput Investigation of Human Genes and Variants Affecting LDL Cholesterol Uptake

Introduction: Genetic differences in cholesterol metabolism are major contributors to the risk of coronary artery disease (CAD), which is the leading cause of death in the USA. Genome-wide association screens have identified over 300 independent genomic loci where genetic variation is associated with serum LDL cholesterol (LDL-C) levels. While several of these loci are important drug targets, for the vast majority of loci, it is unknown which exact genetic variants, genes and cellular pathways are impacted by these variants. Hypothesis: We hypothesize that combining high-throughput CRISPR-Cas9 screening, gene clustering and network analysis, and human genetic biobank cohort analysis will increase our power to reveal the genetic basis behind human variation in cholesterol levels. Methods: We have devised sensitive high-throughput CRISPR-Cas9-based screens to gain insight into the genetic mechanisms that impact cellular cholesterol metabolism. Results: Through a combination of CRISPR-Cas9-nuclease and CRISPR base editing screens, we have identified hundreds of human genes and GWAS-associated variants that influence cellular LDL-C uptake in liver cells. We have developed experimental and computational methods to group these genes into biological pathways, uncovering previously unappreciated cellular mechanisms driving variation in LDL-C uptake. We have connected these novel LDL-C uptake-altering genes and pathways to serum LDL-C levels by analyzing rare coding variant burden from a UK Biobank exome sequencing cohort, identifying functional gene modules for which damaging coding variants in the population have significant effects LDL-C levels. Finally, we have identified GWAS-associated non-coding variants that alter LDL-C uptake through modulating expression of previously unappreciated cholesterol-related genes. Conclusions: Through high-throughput CRISPR screening followed by mechanistic follow-up, we have made progress in dissecting the non-coding loci, genes, and pathways that underlie variation in human cellular cholesterol uptake.

Formulation and Evaluation of Clindamycin phosphate Niosomes by using Reverse Phase Evaporation Method

The formulate and evaluate Niosome drug delivery system for Clindamycin phosphate to increase its effectiveness by increasing penetration through skin and reducing its side effects Sorbitan esters which are Non-ionic surfactants was the key ingredient which forms vesicles upon hydration with aqueous media. Cholesterol was used to make vesicle stable and rigid. Different formulations were preparing by using different sorbitan ester and changing the ratio of surfactant and Cholesterol. Clindamycin Phosphate is an antibiotic widely used for the treatment of acne. The pseudomonas colitis occurs with oral dosage form while in topical dosage forms it has side effects like irritation, skin rash, itching etc. its topical bioavailability is also less. An attempt has been made to overcome these limitations for the preparation to prepare niosomes of clindamycin phosphate as well as for the enhanced delivery through skin by the variation in cholesterol level. Niosome were prepared by reverse phase evaporation method using span 60 as polymer. The compatibility of drug and polymer is analyzed by using FTIR and DSC method. There was no interaction detected by FTIR, DSC study. Further the prepared niosomes were evaluated for drug entrapment efficiency, drug content, and in vitro drug release. Amongst all the formulation batch 3 shows the best release when compared to other batch. SEM (Scanning electron microscopy) revealed that niosomes were spherical and porous. Finally it was concluded that clindamycin phosphate have been found suitable for controlled release formulation due to its bioavailability and biodegradability and thus lead to improved patient compliance.

Cholesterol Metabolism in T Cells.

Compartmentalization and spatial control of biochemical reactions is the foundation of cell-based life on earth. The lipid bilayer system employed by eukaryote cells not only keeps them separate from the environment but also provides a platform for key receptors to sense and interact with outside factors. Arguably one of the cell types most reliant on interactions of this kind, immune cells depend on their membrane to keep functioning properly. In this review, the influence of variation in cholesterol levels, a key component of lipid bilayer stability, on T cells will be discussed in detail. In comparison to other cells, T cells must be able to undergo rapid activation followed by proliferation. Furthermore, receptor colocalization is an important mechanism in this activation process. The impact of cholesterol availability on the processes of T cell proliferation and receptor sensitivity, as well as its potential for immunomodulation in disease treatment will be considered.

Cholesterol variability and the risk of mortality, myocardial infarction, and stroke: a nationwide population-based study.

A high visit-to-visit variability in cholesterol levels has been suggested to be an independent predictor of major adverse cardiovascular events in patients with coronary artery disease (CAD). Because whether this notion applies to general population is not known, we aimed to investigate the associations between total cholesterol (TC) variability and the risk of all-cause mortality, myocardial infarction (MI), and stroke. We identified 3 656 648 subjects without a history of MI and stroke who underwent ≥3 health examinations from 2002 to 2007 in the Korean National Health Insurance System cohort. Total cholesterol variability was measured using the coefficient of variation (CV), standard deviation (SD), and variability independent of the mean (VIM). There were 84 625 deaths (2.3%), 40 991 cases of MI (1.1%), and 42 861 cases of stroke (1.2%) during the median follow-up of 8.3 years. There was a linear association between higher TC variability and outcome measures. In the multivariable adjusted model, the hazard ratios and 95% confidence intervals comparing the highest vs. lowest quartiles of CV of TC were 1.26 (1.24-1.28) for all-cause mortality, 1.08 (1.05-1.11) for MI, and 1.11 (1.08-1.14) for stroke, which was independent of mean TC levels and the use of lipid-lowering agents. The results were consistent when modelling variability of TC using SD and VIM, and in various sensitivity analyses. High variability in lipid levels is associated with adverse health-related outcomes. These findings suggest that lipid variability is an important risk factor in the general population.

Unusual Detection of Lathosterol in Amniotic Fluids Investigated for the Determination of Cholesterol and 7-Dehydrocholesterol for Suspected Smith-Lemli-Opitz Syndrome

The Smith-Lemli-Opitz syndrome (SLOS), is an autosomal recessive disorder caused by a 7-dehydrocholesterol reductase deficiency, which is characterized by abnormally elevated amniotic fluid 7-DHC (7-dehydrocholesterol) concentrations. A GC/FID (gas-chromatography with a flame ionization detector) and GC/MS (gas-chromatography with a mass detector) method was optimized for the detection of cholesterol and 7-DHC in amniotic fluids. The quantitative determination of cholesterol in 39 control amniotic fluids evidenced that between the fourth and fifth month of pregnancy the levels of this analyte are quite constant, the concentration of total and free cholesterol being respectively 10.3 μg·mL﹣1 (SD = ±3.6) and 1.7 μg·mL﹣1 (SD = ±0.91), while the analysis of 60 amniotic fluids potentially related to SLOS, showed a higher variability of cholesterol levels. Moreover, in 13 samples an analyte which did not correspond either to cholesterol or to 7-DHC was detected. A GC/MS investigation allowed us to identify this compound as lathosterol, a precursor of cholesterol in the biosynthetic pathway.

The Response of the Prostate to Circulating Cholesterol: Activating Transcription Factor 3 (ATF3) as a Prominent Node in a Cholesterol-Sensing Network

Elevated circulating cholesterol is a systemic risk factor for cardiovascular disease and metabolic syndrome, however the manner in which the normal prostate responds to variations in cholesterol levels is poorly understood. In this study we addressed the molecular and cellular effects of elevated and suppressed levels of circulating cholesterol on the normal prostate. Integrated bioinformatic analysis was performed using DNA microarray data from two experimental formats: (1) ventral prostate from male mice with chronically elevated circulating cholesterol and (2) human prostate cells exposed acutely to cholesterol depletion. A cholesterol-sensitive gene expression network was constructed from these data and the transcription factor ATF3 was identified as a prominent node in the network. Validation experiments confirmed that elevated cholesterol reduced ATF3 expression and enhanced proliferation of prostate cells, while cholesterol depletion increased ATF3 levels and inhibited proliferation. Cholesterol reduction in vivo alleviated dense lymphomononuclear infiltrates in the periprostatic adipose tissue, which were closely associated with nerve tracts and blood vessels. These findings open new perspectives on the role of cholesterol in prostate health, and provide a novel role for ATF3, and associated proteins within a large signaling network, as a cholesterol-sensing mechanism.

Natural vs. Drug-Modified Cholesterol Levels and the Incidence of Ischemic Stroke (P06.228)

Objective: To determine whether naturally low LDL and high HDL levels are associated with a lower incidence of first-time ischemic stroke compared to drug-modified low LDL and high HDL levels. Background High LDL and low HDL levels have been associated with a higher risk of ischemic stroke. However, most studies investigating this relationship are a subset of drug clinical trials where variation in cholesterol levels is considered only as a factor in drug-related reduction of stroke incidence. Clinical observation reveals that patients with a very low burden of cerebrovascular disease share low LDL and high HDL levels and, frequently, these patients are not taking any cholesterol-modifying drug. Design/Methods: In this cross-sectional study we included patients 55 years or older admitted to an academic institution with a diagnosis of ischemic stroke (stroke) or any other diagnosis (control) and who had MRI brain with diffusion-weighted and T2/FLAIR sequences. We excluded patients who had negative DWI (stroke group) or T2/FLAIR lesions suggestive of previous stroke as well as patients with a reported history of stroke. Univariate analysis and logistic regression were performed for statistical analysis. Results: Older age, hypertension, atrial fibrillation, higher LDL and triglycerides levels were associated with increased incidence of ischemic stroke in the univariate analysis. In the logistic regression analysis, after matching LDL values and age, patients who were on cholesterol-modifying drugs had a lower incidence of ischemic stroke compared to patients who weren9t. After dividing LDL levels in 3 groups, the preventive effect of not being on a cholesterol-modifying drug was strong and significant in the group with the lowest LDL values ( Conclusions: Patients in the group with the lowest LDL-cholesterol who are not on a cholesterol-modifying drug (i.e who have naturally low LDL-cholesterol) have a lower incidence of first-time ischemic stroke compared to patients who have drug-modified low LDL-cholesterol levels. Disclosure: Dr. Osorio Flores has nothing to disclose. Dr. Venkatesh has nothing to disclose.

Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease--a Mendelian Randomisation study.

BackgroundRare mutations of the low-density lipoprotein receptor gene (LDLR) cause familial hypercholesterolemia, which increases the risk for coronary artery disease (CAD). Less is known about the implications of common genetic variation in the LDLR gene regarding the variability of cholesterol levels and risk of CAD.MethodsImputed genotype data at the LDLR locus on 1 644 individuals of a population-based sample were explored for association with LDL-C level. Replication of association with LDL-C level was sought for the most significant single nucleotide polymorphism (SNP) within the LDLR gene in three European samples comprising 6 642 adults and 533 children. Association of this SNP with CAD was examined in six case-control studies involving more than 15 000 individuals.FindingsEach copy of the minor T allele of SNP rs2228671 within LDLR (frequency 11%) was related to a decrease of LDL-C levels by 0.19 mmol/L (95% confidence interval (CI) [0.13–0.24] mmol/L, p = 1.5×10−10). This association with LDL-C was uniformly found in children, men, and women of all samples studied. In parallel, the T allele of rs2228671 was associated with a significantly lower risk of CAD (Odds Ratio per copy of the T allele: 0.82, 95% CI [0.76–0.89], p = 2.1×10−7). Adjustment for LDL-C levels by logistic regression or Mendelian Randomisation models abolished the significant association between rs2228671 with CAD completely, indicating a functional link between the genetic variant at the LDLR gene locus, change in LDL-C and risk of CAD.ConclusionA common variant at the LDLR gene locus affects LDL-C levels and, thereby, the risk for CAD.

Cholesterol tracking from childhood to adult mid-life in children from the Busselton study

To determine if subjects' cholesterol levels tracked relative to their peers from early childhood to adult mid-life. Longitudinal study using subjects from the Busselton Population Study. Data were available from 1967 on a triennial basis until 1983, and a re-survey held in 1994. The study included 1764 subjects aged 5-18 y at first measurement. Pearson's correlation coefficient, adjusted for age and survey year, was used to examine cholesterol tracking. The proportion of children who persisted with cholesterol measurements in the extreme high quartile was assessed over time before and after adjusting data for regression to the mean. The variability of the children's cholesterol level was examined by track width using the method of Porkka. The correlation coefficients for tracking were from 0.35 to 0.55. Stronger correlations coincided with shorter time periods between measurements. Before adjustment for regression to the mean, 55-60% of children from the highest quartile at first measurement remained in the same quartile 27 y later. After adjustment for regression to the mean, the number of children with levels in the extreme high quartile decreased, but 80% of these persisted in that quartile. Intra-individual variations in cholesterol levels have an important influence on population tracking levels and need to be considered when interpreting tracking results from early childhood to adult mid-life. However, removing the effect of regression to the mean by taking multiple measurements of cholesterol will probably improve prediction for individuals.

α-Tocopherol levels in plasma in new-onset, insulin-dependent diabetes mellitus

Background Diabetic complications have been related to increased oxidative stress. Plasma antioxidant levels may be affected by hyperglycemia-induced oxidative stress as well as by insulin therapy. We evaluated the immediate effect of insulin treatment and improved metabolic control on the important antioxidant α-tocopherol plasma (vitamin E) levels in new-onset, insulin-dependent diabetes mellitus. Methods The study was performed in 15 consecutive patients, aged 20–67 years, with new-onset diabetes mellitus requiring acute insulin treatment. Plasma α-tocopherol levels were measured before the start of intensive insulin treatment and monthly for 6 months thereafter. Simultaneously, we studied plasma malondialdehyde (MDA) as a reflection of lipid peroxidation. In addition, comparisons were made to a nondiabetic reference group. Results Baseline α-tocopherol levels did not differ from those in nondiabetic subjects. α-Tocopherol decreased significantly, from 33.5±12.1 μmol/l before treatment to 28.11±6.85 μmol/l (−16%) after 1 month of insulin therapy ( p<0.04) to 26.6±7.03 μmol/l (−20%) after 3 months of insulin therapy ( p<0.02). This trend did not change after adjusting for variations in cholesterol levels. After 6 months, α-tocopherol was no longer decreased compared to baseline levels (29.6±7.4 μmol/l). MDA concentrations at baseline were significantly higher in the diabetic patients (3.79±2.91 μmol/l) than in the nondiabetic subjects (1.57±0.21 μmol/l, p=0.006). MDA concentrations decreased significantly following the start of insulin treatment. Conclusions Patients with new-onset, insulin-dependent diabetes mellitus have α-tocopherol levels that are similar to those in normal subjects. Insulin treatment and/or improved metabolic control cause a significant decrease in α-tocopherol levels during the first months.

The Diet1 Locus Confers Protection against Hypercholesterolemia through Enhanced Bile Acid Metabolism

The C57BL/6ByJ (B6By) mouse strain is resistant to diet-induced hypercholesterolemia and atherosclerosis, despite its near genetic identity with the atherosclerosis-susceptible C57BL/6J (B6J) strain. We previously identified a genetic locus, Diet1, which is responsible for the resistant phenotype in B6By mice. To investigate the function of Diet1, we compared mRNA expression profiles in the liver of B6By and B6J mice fed an atherogenic diet using a DNA microarray. These studies revealed elevated expression levels in B6By liver for key bile acid synthesis proteins, including cholesterol 7alpha-hydroxylase and sterol-27-hydroxylase, and the oxysterol nuclear receptor liver X receptor alpha. Expression levels for several other genes involved in bile acid metabolism were subsequently found to differ between B6By and B6J mice, including the bile acid receptor farnesoid X receptor, oxysterol 7alpha-hydroxylase, sterol-12alpha-hydroxylase, and hepatic bile acid transporters on both sinusoidal and canalicular membranes. The overall expression profile of the B6By strain suggests a higher rate of bile acid synthesis and transport in these mice. Consistent with this interpretation, fecal bile acid excretion is increased 2-fold in B6By mice, and bile acid levels in blood and urine are elevated 3- and 18-fold, respectively. Genetic analysis of serum bile acid levels revealed co-segregation with Diet1, indicating that this locus is likely responsible for both increased bile acid excretion and resistance to hypercholesterolemia in B6By mice.

Ionizing radiation and genetic risks

This paper provides a broad overview of the epidemiological and genetical aspects of common multifactorial diseases in man with focus on three well-studied ones, namely, coronary heart disease (CHD), essential hypertension (EHYT) and diabetes mellitus (DM). In contrast to mendelian diseases, for which a mutant gene either in the heterozygous or homozygous condition is generally sufficient to cause disease, for most multifactorial diseases, the concepts of genetic susceptibility' and risk factors' are more appropriate. For these diseases, genetic susceptibility is heterogeneous. The well-studied diseases such as CHD permit one to conceptualize the complex relationships between genotype and phenotype for chronic multifactorial diseases in general, namely that allelic variations in genes, through their products interacting with environmental factors, contribute to the quantitative variability of biological risk factor traits and thus ultimately to disease outcome. Two types of such allelic variations can be distinguished, namely those in genes whose mutant alleles have (i) small to moderate effects on the risk factor trait, are common in the population (polymorphic alleles) and therefore contribute substantially to the variability of biological risk factor traits and (ii) profound effects, are rare in the population and therefore contribute far less to the variability of biological risk factor traits. For all the three diseases considered in this review, a positive family history is a strong risk factor. CHD is one of the major contributors to mortality in most industrialized countries. Evidence from epidemiological studies, clinical correlations, genetic hyperlipidaemias etc., indicate that lipids play a key role in the pathogenesis of CHD. The known lipid-related risk factors include: high levels of low density lipoprotein cholesterol, low levels of high density lipoprotein cholesterol, high apoB levels (the major protein fraction of the low density lipoprotein particles) and elevated levels of Lp(a) lipoprotein. Among the risk factors which are not related to lipids are: high levels of homocysteine, low activity of paraoxonase and possibly also elevated plasma fibrinogen levels. In addition to the above, hypertension, diabetes and obesity (which themselves have genetic determinants) are important risk factors for CHD. Among the environmental risk factors are: high dietary fat intake, smoking, stress, lack of exercise etc. About 60% of the variability of the plasma cholesterol is genetic in origin. While a few genes have been identified whose mutant alleles have large effects on this trait (e.g., LDLR, familial defective apoB-100), variability in cholesterol levels among individuals in most families is influenced by allelic variation in many genes (polymorphisms) as well as environmental exposures. A proportion of this variation can be accounted for by two alleles of the apoE locus that increase (&epsi;4) and decrease (&epsi;2) cholesterol levels, respectively. A polymorphism at the apoB gene (XbaI) also has similar effects, but is probably not mediated through lipids. High density lipoprotein cholesterol levels are genetically influenced and are related to apoA1 and hepatic lipase (LIPC) gene functions. Mutations in the apoA1 gene are rare and there are data which suggest a role of allelic variation at or linked LIPC gene in high density lipoprotein cholesterol levels. Polymorphism at the apoA1--C3 loci is often associated with hypertriglyceridemia. The apo(a) gene which codes for Lp(a) is highly polymorphic, each allele determining a specific number of multiple tandem repeats of a unique coding sequence known as Kringle 4. The size of the gene correlates with the size of the Lp(a) protein. The smaller the size of the Lp(a) protein, the higher are the Lp(a) levels. (ABSTRACT TRUNCATED)

New Focus on 'Normal' LDL Levels May Allow Development of Cardiac Disease Risk Prediction

THE 80-YEAR-OLD patient appeared be at high risk for myocardial infarction. Diagnosed with heterozygous familial hypercholesterolemia, the woman had a cholesterol level above 10.3 mmol/L (400 mg/dL)—and had for her entire life, as far as anyone knew. So what brought her the hospital? She was having cosmetic surgery on her ankles so she could fit into her ballet slippers again, recalled Michael S. Brown, MD. She'd never had a heart attack in her life. On the other hand, noted Brown, a 1985 Nobel laureate who is professor of medical genetics at University of Texas Southwestern Medical Center in Dallas, it's far from unusual to see people with cholesterol levels of 200 mg/dL [5.2 mmol/L] having heart attacks. The enormous variations in cholesterol levels and their role in causing coronary artery disease were discussed during Brown's presentation at the annual meeting of the American Association for Clinical Chemistry/Canadian Society

Incomplete dominance of type III hyperlipoproteinemia is associated with the rare apolipoprotein E2 (Arg136 → Ser) variant in multigenerational pedigree studies

In the process of screening apolipoprotein (apo) E genotypes in a population of subjects with lipid abnormalities, we have identified five subjects (one homozygote and four heterozygotes) with an abnormal 109 base pairs band following apo E restriction isotyping of amplified DNA with the restriction endonuclease CfoI. The polymerase chain reaction (PCR) products were cloned and their sequencing revealed a C → A substitution at the first nucleotide of codon 136. This mutation resulted in an amino acid substitution Arg to Ser, previously described as apo E2 Christchurch. Family studies were carried out for four of the probands. In these kindreds, stepwise multiple regression analyses indicated that 78% of the cholesterol variability in men was predicted by body mass index, age and the rare apo E2 (Arg136 → Ser) variant. In women, age and the apo E2 (Arg136 → Ser) variant predicted 54.9% of the variability in cholesterol levels. Linkage analysis suggested that the presence of the apo E2 (Arg136 → Ser) variant was linked with the occurrence of cholesterol enriched triglyceride rich lipoproteins and with an incomplete dominance of type III hyperlipoproteinemia. Our data indicates that this mutation may be a relatively common cause of dyslipidemia in the Spanish population.

Year-to-Year Variability of Cholesterol Levels in a Pediatric Practice

To study the impact of the variability of blood cholesterol levels, which are known to vary spontaneously. The impact of this variability on screening for hypercholesterolemia according to National Cholesterol Education Program (NCEP) guidelines was reviewed in a private pediatric practice. Retrospective chart review. Private pediatric practice. Children (N = 646) aged 3 to 19 years. Cholesterol measurements at a mean interval of 19 months between visits. Year-to-year change in cholesterol levels according to NCEP guidelines, regression to the mean, age, pubertal status, body mass index, hematocrit, interval between measurements, and season of the year were assessed for their contribution to cholesterol level variability. Cholesterol level varied significantly with both age (P < .001) and pubertal status (P < .01) with children aged 9 to 12 years; prepubertal children had the highest levels. Visit-to-visit consistency of NCEP classification was poorer for younger children than for older children (kappa = 0.21 for 3- to 6-year-olds, 0.39 for 6- to 10-year-olds, and 0.44 for those older than 10 years). Of children with initial total cholesterol levels of 5.17 mmol/L (200 mg/dL) or greater, only 40% continued to have high levels at follow-up. A child with an initial cholesterol value of 5.17 mmol/L (200 mg/dL) showed an average decline of 0.34 mmol/L (13 mg/dL) at follow-up by regression analysis. Year-to-year variability in total cholesterol level has a significant impact on the stability of NCEP classification.