Genetic Epidemiology and Lipids: A Pattern So Grand and Complex

Intensive research over the course of the last several decades led to dramatic improvements in understanding, treating, and preventing cardiovascular disease. Despite this progress, cardiovascular disease remains the leading cause of mortality in both high- and low-income countries, and the leading source of morbidity in high-income countries. Lipids are well known determinants of cardiovascular disease risk; epidemiological evidence was published long ago. Total cholesterol and low-density lipoprotein cholesterol (LDL), which tend to be strongly correlated, are associated with increased disease risk. LDL can be readily oxidized, which causes inflammation and atherosclerosis to occur, and small, dense LDL particles are considered the most atherogenic lipid particles. High-density lipoprotein cholesterol (HDL), by contrast, is associated with beneficial effects, in terms of cardiovascular disease risk. Several mechanisms are likely to account for the protective consequences of increased HDL concentrations. HDL exhibits anti-inflammatory properties. Additionally, it is thought to be an anti-oxidant, helping to offset the deleterious effects of oxidized LDL. HDL is also involved in reverse cholesterol transp

Length-weight relationships for some important forage crustaceans from South Africa

The diet of marine animals is usually determined by stomach content analysis. Although partially digested prey fragments can often be identified to species level, it is difficult to estimate the original mass of the prey organism. This information, however, is essential for calculating both the total food intake as well as the relative contribution of each prey item. In this study we present regression equations that can be used to estimate the original mass of 18 common South African crustaceans from various indigestible fragments such as the carapace (length and width), chelae (length and width of left and right dactylus) and eye (length and width)

Rethinking pediatric ethics consultations

Johnson and colleagues (2015) report a retrospective review of the experience of an ethics consultation service at a single, highly specialized children's hospital over an 11-year period. Despite its methodologic limitations, the results of this study are worthy of note. The St. Jude Children's Research Hospital ethics consultation service consulted on a range of complex cases, including the management of conflict between parents and physicians, futility, parental demands, treatment nonadherence, and, less commonly, end-of-life issues. The number of case consultations was small, fewer than five per year, and did not increase over time. The retrospective nature of the study prevented eliciting how often consultations altered treatment or other decisions. No record was kept of clinical staff, parent, or patient perception of the value of the ethics consultation, nor of the frequency or value of informal (curb side) ethics consultations. The St. Jude ethics consultation process is consistent with “standard” models in the field. An ethics team comprising two to five staff members, including an ethicist, performs the initial ward consultation, which is then discussed with the formal clinical ethics committee of 21 people. Other involved services participate via interdisciplinary meetings. The types of consultation are consistent with many other services, including both formal and informal consultations using a range of methods to assist resolution of cases, including mediation and arbitration. Despite open access to requesting consultations, including anonymous enquiries, almost all requests came from physicians, often the same ones. Only a few came from nurses and none from parents or patients. Importantly, nurses appeared to be subject to repercussions from physicians if they requested consultations, an important issue that requires further attention but goes beyond the scope of our commentary. We suggest that the experience of the St. Jude service illustrates both the limitations of ethics consultation and the need to evaluate the importance and impact of an ethics service using metrics other than simply the number of case consultations

Real-time PCR based on SYBR-Green I fluorescence: An alternative to the TaqMan assay for a relative quantification of gene rearrangements, gene amplifications and micro gene deletions

BACKGROUND: Real-time PCR is increasingly being adopted for RNA quantification and genetic analysis. At present the most popular real-time PCR assay is based on the hybridisation of a dual-labelled probe to the PCR product, and the development of a signal by loss of fluorescence quenching as PCR degrades the probe. Though this so-called 'TaqMan' approach has proved easy to optimise in practice, the dual-labelled probes are relatively expensive. RESULTS: We have designed a new assay based on SYBR-Green I binding that is quick, reliable, easily optimised and compares well with the published assay. Here we demonstrate its general applicability by measuring copy number in three different genetic contexts; the quantification of a gene rearrangement (T-cell receptor excision circles (TREC) in peripheral blood mononuclear cells); the detection and quantification of GLI, MYC-C and MYC-N gene amplification in cell lines and cancer biopsies; and detection of deletions in the OPA1 gene in dominant optic atrophy. CONCLUSION: Our assay has important clinical applications, providing accurate diagnostic results in less time, from less biopsy material and at less cost than assays currently employed such as FISH or Southern blotting

Failing beta-cell adaptation in South Asian families with a high risk of type 2 diabetes

We performed an extended oral glucose tolerance test (OGTT) to investigate the relationship between early and late beta-cell response and type 2 diabetes (T2D) in families of South Asian origin and indigenous Dutch, burdened by T2D. Based on the OGTT, 22 individuals were normoglycemic, 12 glucose intolerant and 23 had T2D in the South Asian families; these numbers were 34, 12 and 18 in the Caucasian families, respectively. The OGTT had 11 blood samplings in 3.5 h for glucose, insulin and C-peptide measurements. Through early and late insulin secretion rate (ISR), the above basal glucose area-under-the-curve after glucose load (glucose disposal) and insulin sensitivity index (ISI), we obtained early and late disposition indices (DI). South Asians on average had lower ISI than Caucasians (3.8 ± 2.9 vs. 6.5 ± 4.7, respectively, P < 0.001), with rapid decline of their early and late DI between normal glucose tolerance versus impaired fasting glucose/impaired glucose tolerance (late DI; P < 0.0001). Adjusted for ISI, age, gender and waist-to-hip ratio, early ISR was significantly associated with glucose disposal in South Asians (β = 0.55[0.186; 0.920]), but not in Caucasians (β = 0.09[-0.257; 0.441]). Similarly, early ISR was strongly associated with late ISR (β = 0.71[0.291; 1.123]; R2 = 45.5 %) in South Asians, but not in Caucasians (β = 0.27[-0.035; 0.576]; R2 = 17.4 %), with significant interaction between ethnicity and early ISR (β = 0.341[0.018; 0.664]). Ordinal regression analyses confirmed that all South Asian OGTT subgroups were homogenously resistant to insulin and solely predicted by early ISR (β = -0.782[-1.922; 0.359], β = -0.020[-0.037; -0.002], respectively), while in Caucasian families both ISI and early ISR were related to glucose tolerance state (β = -0.603[-1.105; -0.101], β = -0.066[-0.105; -0.027], respectively). In South Asian individuals, rapid beta-cell deterioration might occur under insulin resistant conditions. As their early insulin response correlates strongly with both glucose disposal and late insulin response, alterations in beta-cell dynamics may give an explanation to their extreme early onset of T2D, although larger prospective studies are required

Heritabilities, proportions of heritabilities explained by GWAS findings, and implications of cross-phenotype effects on PR interval

Electrocardiogram (ECG) measurements are a powerful tool for evaluating cardiac function and are widely used for the diagnosis and prediction of a variety of conditions, including myocardial infarction, cardiac arrhythmias, and sudden cardiac death. Recently, genome-wide association studies (GWASs) identified a large number of genes related to ECG parameter variability, specifically for the QT, QRS, and PR intervals. The aims of this study were to establish the heritability of ECG traits, including indices of left ventricular hypertrophy, and to directly assess the proportion of those heritabilities explained by GWAS variants. These analyses were conducted in a large, Dutch family-based cohort study, the Erasmus Rucphen Family study using variance component methods implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) software package. Heritability estimates ranged from 34 % for QRS and Cornell voltage product to 49 % for 12-lead sum. Trait-specific GWAS findings for each trait explained a fraction of their heritability (17 % for QRS, 4 % for QT, 2 % for PR, 3 % for Sokolow–Lyon index, and 4 % for 12-lead sum). The inclusion of all ECG-associated single nucleotide polymorphisms explained an additional 6 % of the heritability of PR. In conclusion, this study shows that, although GWAS explain a portion of ECG trait variability, a large amount of heritability remains to be explained. In addition, larger GWAS for PR are likely to detect loci already identified, particularly those observed for QRS and 12-lead sum

Compton scattering beyond the impulse approximation

We treat the non-relativistic Compton scattering process in which an incoming photon scatters from an N-electron many-body state to yield an outgoing photon and a recoil electron, without invoking the commonly used frameworks of either the impulse approximation (IA) or the independent particle model (IPM). An expression for the associated triple differential scattering cross section is obtained in terms of Dyson orbitals, which give the overlap amplitudes between the N-electron initial state and the (N-1) electron singly ionized quantum states of the target. We show how in the high energy transfer regime, one can recover from our general formalism the standard IA based formula for the cross section which involves the ground state electron momentum density (EMD) of the initial state. Our formalism will permit the analysis and interpretation of electronic transitions in correlated electron systems via inelastic x-ray scattering (IXS) spectroscopy beyond the constraints of the IA and the IPM.Comment: 7 pages, 1 figur

A combined linkage and exome sequencing analysis for electrocardiogram parameters in the Erasmus Rucphen family study

Electrocardiogram (ECG) measurements play a key role in the diagnosis and prediction of cardiac arrhythmias and sudden cardiac death. ECG parameters, such as the PR, QRS, and QT intervals, are known to be heritable and genome-wide association studies of these phenotypes have been successful in identifying common variants; however, a large proportion of the genetic variability of these traits remains to be elucidated. The aim of this study was to discover loci potentially harboring rare variants utilizing variance component linkage analysis in 1547 individuals from a large family-based study, the Erasmus Rucphen Family Study (ERF). Linked regions were further explored using exome sequencing. Five suggestive linkage peaks were identified: two for QT interval (1q24, LOD = 2.63; 2q34, LOD = 2.05), one for QRS interval (1p35, LOD = 2.52) and two for PR interval (9p22, LOD = 2.20; 14q11, LOD = 2.29). Fine-mapping using exome sequence data identified a C > G missense variant (c.713C > G, p.Ser238Cys) in the FCRL2 gene associated with QT (rs74608430; P = 2.8 × 10-4, minor allele frequency = 0.019). Heritability analysis demonstrated that the SNP explained 2.42% of the trait's genetic variability in ERF (P = 0.02). Pathway analysis suggested that the gene is involved in cytosolic Ca2+ levels (P = 3.3 × 10-3) and AMPK stimulated fatty acid oxidat

A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy

Background: Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them. Methods: The study was conducted among participants from the Erasmus Rucphen Family Study (ERF), a Dutch family-based sample from the southwestern Netherlands. Variance components linkage analyses were performed using Merlin. Regions of interest (LOD > 1.9) were fine-mapped using microarray and exome sequence data. Results: We observed one significant LOD score for the second principal component on chromosome 15 (LOD score = 3.01) and 12 suggestive LOD scores. Several loci contained variants identified in GWAS for these traits; however, these did not explain the linkage peaks, nor did other common variants. Exome sequence data identified two associated variants after multiple testing corrections were applied. Conclusions: We did not find common SNPs explaining these linkage signals. Exome sequencing uncovered a relatively rare variant in MAPK3K11 on chromosome 11 (MAF = 0.01) that helped account for the suggestive linkage peak observed for the first principal component. Conditional analysis revealed a drop in LOD from 2.01 to 0.88 for MAP3K11, suggesting that this variant may partially explain the linkage signal at this chromosomal location. MAP3K11 is related to the JNK pathway and is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies, including LVH