The Atherogenic Dyslipidemia Complex and Novel Approaches to Cardiovascular Disease Prevention in Diabetes.

Despite the effectiveness of low-density lipoprotein (LDL)-lowering strategies for the treatment of diabetic dyslipidemia, significant residual risk of atherosclerotic cardiovascular disease remains. Residual risk might in part be explained by lipid abnormalities that go beyond LDL cholesterol elevation, collectively termed the "atherogenic dyslipidemia complex (ADC)," consisting of hypertriglyceridemia, elevated small dense LDL particles, reduced high-density lipoprotein cholesterol, and high-density lipoprotein particle numbers, increased remnant lipoproteins, and postprandial hyperlipidemia. In this review, we briefly discuss the pathophysiology of the typical dyslipidemia that occurs in insulin-resistant states including obesity, the metabolic syndrome, and type 2 diabetes.

A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype.

Background: Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec.

Niacin: another look at an underutilized lipid-lowering medication.

Niacin, or water-soluble vitamin B(3), when given at pharmacologic doses, is a powerful lipid-altering agent. This drug, which lowers the levels of atherogenic, apolipoprotein-B-containing lipoproteins, is one of few medications that can raise the levels of atheroprotective HDL cholesterol. Niacin also has beneficial effects on other cardiovascular risk factors, including lipoprotein(a), C-reactive protein, platelet-activating factor acetylhydrolase, plasminogen activator inhibitor 1 and fibrinogen.

Lipoprotein(a): more interesting than ever after 50 years.

Purpose Of Review: Lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease; we highlight the most recent research initiatives that have sought to define Lp(a)-dependent pathogenicity as well as pharmacologic approaches to lowering Lp(a).

Recent Findings: Recent large-scale meta-analyses have confirmed elevated Lp(a) concentrations to be a moderate but consistent prospective coronary heart disease (CHD) risk factor. The Mendelian randomization approach has also associated LPA variants with Lp(a) concentration and CHD risk.

Genetic bases of hypertriglyceridemic phenotypes.

Purpose Of Review: Hypertriglyceridemia (HTG) is a common diagnosis. Although secondary factors are important for clinical expression, susceptibility to HTG has a strong genetic component, which we review here.

Recent Findings: Severe HTG in a few families follows Mendelian - typically autosomal recessive - inheritance of rare loss-of-function mutations in genes such as LPL, APOC2, APOA5, LMF1, and GPIHBP1.

Sortilin: an unusual suspect in cholesterol metabolism: from GWAS identification to in vivo biochemical analyses, sortilin has been identified as a novel mediator of human lipoprotein metabolism.

The concentration of low-density lipoprotein (LDL) cholesterol (C) in plasma is a key determinant of cardiovascular disease risk and human genetic studies have long endeavoured to elucidate the pathways that regulate LDL metabolism. Massive genome-wide association studies (GWASs) of common genetic variation associated with LDL-C in the population have implicated SORT1 in LDL metabolism. Using experimental paradigms and standards appropriate for understanding the mechanisms by which common variants alter phenotypic expression, three recent publications have presented divergent and even contradictory findings.

Anacetrapib: hope for CETP inhibitors?

Inhibition of cholesteryl ester transfer protein (CETP), a key protein involved in reverse cholesterol transport, can lead to increases in high-density lipoprotein cholesterol (HDL-C) levels and thus, is under evaluation as an antiatherogenic strategy. Several CETP inhibitors have been under development including anacetrapib, dalcetrapib, and torcetrapib. To date, anacetrapib demonstrates the greatest HDL-C raising and low-density lipoprotein cholesterol (LDL-C) lowering potential.

Advances in genomic analysis of stroke: what have we learned and where are we headed?

As a result of technological advances, the genomic analysis of stroke has shifted from candidate gene association studies to genome-wide association studies (GWAS). Agnostic GWAS evaluate up to 90% of common genetic variation in a single experiment, creating an improved framework for identifying novel genetic leads for biochemical and cellular mechanisms underlying stroke. Given the ubiquity of the GWAS approach, it has become essential for stroke researchers and clinicians to be able to interpret GWAS results.

A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia.

Numerous single nucleotide polymorphisms (SNPs) have been found in recent genome wide association studies (GWAS) to be associated with subtle plasma triglyceride (TG) variation in normolipidemic subjects. However, since these GWAS did not specifically evaluate patients with rare disorders of lipoprotein metabolism--'hyperlipoproteinemia' (HLP)--it remains largely unresolved whether any of these SNP determinants of modest physiological changes in TG are necessarily also determinants of most HLP phenotypes. To address this question, we evaluated 28 TG-associated SNPs from GWAS in 386 unrelated adult patients with one of five Fredrickson phenotypes (HLP types 2A, 2B, 3, 4 and 5) and 242 matched normolipidemic controls.

Narrative review: statin-related myopathy.

Statin-related myopathy is a clinically important cause of statin intolerance and discontinuation. The spectrum of statin-related myopathy ranges from common but clinically benign myalgia to rare but life-threatening rhabdomyolysis. Observational studies suggest that myalgia can occur in up to 10% of persons prescribed statins, whereas rhabdomyolysis continues to be rare.

Predicting abdominal adipose tissue among women with familial partial lipodystrophy.

The objective of the study was to determine correlations between magnetic resonance imaging (MRI) measures of truncal adiposity (trunk fat percentage [TrF %(MRI)], visceral adipose tissue [VAT], and subcutaneous abdominal adipose tissue [SAT]), simple clinical measures (body mass index [BMI], waist circumference [WC], and waist-to-hip ratio [WHR]), and bioelectrical impedance analysis (BIA)-derived measures (total fat percentage [TF %] and TrF %(BIA)) in female patients with familial partial lipodystrophy (FPLD). Our secondary aim was to generate and cross-validate predictive equations for VAT and SAT using these simple clinical and BIA-derived variables. Measures of truncal adiposity were measured using 1.

Novel LPL mutations associated with lipoprotein lipase deficiency: two case reports and a literature review.

Lipoprotein lipase (LPL) is a key enzyme involved with hydrolysis and removal of triglycerides from plasma. LPL deficiency is a rare condition with an estimated prevalence of 1 in 106. It is characterized biochemically by elevated triglycerides and lowered HDL in the plasma and clinically by a constellation of signs and symptoms during childhood including failure to thrive, lipemia retinalis, eruptive xanthomas, hepatosplenomegaly, and acute pancreatitis.

Prevalence of reproductive abnormalities among women with familial partial lipodystrophy.

Objective: To compare the risk of having polycystic ovary syndrome (PCOS) or ovarian cysts among women with genetically confirmed familial partial lipodystrophy (FPLD) with that in the general population of healthy women.

Methods: Twenty-five women with FPLD who were 18 to 80 years old were interviewed regarding a history of PCOS or ovarian cysts (composite primary outcome) as well as for secondary outcomes of interest including menstrual irregularities, hirsutism, gynecologic surgical procedures, and fertility or obstetric complications. From the 2005 National Ambulatory Medical Care Survey, 3,326 women, aged 18 to 80 years (control subjects), were assessed for the presence of the primary outcome based on appropriate International Classification of Diseases, Ninth Revision, Clinical Modification codes.

Plasma lipoproteins: genetic influences and clinical implications.

Susceptibility to the growing global public health problem of cardiovascular disease is associated with levels of plasma lipids and lipoproteins. Several experimental strategies have helped us to clarify the genetic architecture of these complex traits, including classical studies of monogenic dyslipidaemias, resequencing, phenomic analysis and, more recently, genome-wide association studies and analysis of metabolic networks. The genetic basis of plasma lipoprotein levels can now be modelled as a mosaic of contributions from multiple DNA sequence variants, both rare and common, with varying effect sizes.

Genetic testing for atherosclerosis risk: inevitability or pipe dream?

Family history is a risk factor for coronary artery disease (CAD). However, defining this risk at the DNA level has been elusive. In 2007, four genome-wide association studies reported a strong association between CAD and a region on chromosome 9p21.

APOA5 genetic variants are markers for classic hyperlipoproteinemia phenotypes and hypertriglyceridemia.

Background: Several known candidate gene variants are useful markers for diagnosing hyperlipoproteinemia. In an attempt to identify other useful variants, we evaluated the association of two common APOA5 single-nucleotide polymorphisms across the range of classic hyperlipoproteinemia phenotypes.

Methods: We assessed plasma lipoprotein profiles and APOA5 S19W and -1131T>C genotypes in 678 adults from a single tertiary referral lipid clinic and in 373 normolipidemic controls matched for age and sex, all of European ancestry.

Polygenic determinants of severe hypertriglyceridemia.

Recent genome-wide association (GWA) studies have identified new genetic determinants of complex quantitative traits, including plasma triglyceride (TG). We hypothesized that common variants associated with mild TG variation identified in GWA studies would also be associated with severe hypertriglyceridemia (HTG). We studied 132 patients of European ancestry with severe HTG (fasting plasma TG > 10 mmol/l), who had no mutations found by resequencing of candidate genes, and 351 matched normolipidemic controls.

The failure of torcetrapib: what have we learned?

The failure of the cholesterol ester transfer protein (CETP) inhibitor, torcetrapib, has led to questions regarding whether the molecule itself or the mechanism of CETP inhibition was responsible for the adverse cardiovascular outcomes. Given the association with increases in blood pressure and plasma aldosterone levels, torcetrapib has been postulated to have adverse 'off-target' effects. In this issue of British Journal of Pharmacology, Forrest and co-workers have elegantly investigated these effects, demonstrating two salient points -- (1) the pressor effect of torcetrapib is independent of CETP inhibition and (2) although associated with hyperaldosteronism, the pressor effect is likely not mediated by hyperaldosteronism.

Is raising HDL a futile strategy for atheroprotection?

The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein inhibitor torcetrapib has led to considerable doubt about the value of raising high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These results have underscored the intricacy of HDL metabolism, with functional quality perhaps being a more important consideration than the circulating quantity of HDL. As a result, HDL-based therapeutics that maintain or enhance HDL functionality warrant closer investigation.

Alstrom syndrome (OMIM 203800): a case report and literature review.

Background: Alstrom syndrome (AS) is a rare autosomal recessive disease characterized by multiorgan dysfunction. The key features are childhood obesity, blindness due to congenital retinal dystrophy, and sensorineural hearing loss. Associated endocrinologic features include hyperinsulinemia, early-onset type 2 diabetes, and hypertriglyceridemia.

Resequencing genomic DNA of patients with severe hypertriglyceridemia (MIM 144650).

Objective: The genetic determinants of severe hypertriglyceridemia (HTG; MIM 144650) in adults are poorly defined. We therefore resequenced 3 candidate genes, namely LPL, APOC2, and APOA5, to search for accumulation of missense mutations in patients with severe HTG compared with normolipidemic subjects.

Methods And Results: We resequenced >2 million base pairs of genomic DNA from 110 nondiabetic patients with severe HTG and determined the prevalence of coding sequence variants compared with 472 age- and sex-matched normolipidemic controls.

Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism.

The lipodystrophies are characterized by loss of adipose tissue in some anatomical sites, frequently with fat accumulation in nonatrophic depots and ectopic sites such as liver and muscle. Molecularly characterized forms include Dunnigan-type familial partial lipodystrophy (FPLD), partial lipodystrophy with mandibuloacral dysplasia (MAD), Berardinelli-Seip congenital generalized lipodystrophy (CGL), and some cases with Barraquer-Simons acquired partial lipodystrophy (APL). The associated mutant gene products include 1) nuclear lamin A in FPLD type 2 and MAD type A; 2) nuclear lamin B2 in APL; 3) nuclear hormone receptor peroxisome proliferator-activated receptor gamma in FPLD type 3; 4) lipid biosynthetic enzyme 1-acylglycerol-3-phosphate O-acyltransferase 2 in CGL type 1; 5) integral endoplasmic reticulum membrane protein seipin in CGL type 2; and 6) metalloproteinase ZMPSTE24 in MAD type B.