Evidence for Genetic Factors Underlying the Insulin Resistance Syndrome in American Indians

Previous analyses of American Indians of the Strong Heart Study have demonstrated that various insulin‐resistance variables cluster, although knowledge about the genetic determination of these clusters is unknown. In an effort to explore the influences on the aggregation of insulin‐resistance phenotypes, we used principal component factor analysis to examine the clustering of these phenotypes in participants of the Strong Heart Family Study and evaluated the genetic and environmental contributions of such factors. Nine traits were chosen for principal component factor analysis: BMI, diastolic blood pressure, fasting glucose, high‐density lipoprotein‐cholesterol, natural log‐transformed insulin, natural log‐transformed triglycerides, percentage of body fat, systolic blood pressure, and waist‐to‐hip ratio. Analyses revealed three clusters: glucose/insulin/obesity, blood pressure, and dyslipidemia factors. Using a variance component approach and accounting for the effects of age, sex, center, and medication, we detected significant heritabilities (h²) for the three factors: h² = 0.67, h² = 0.33, and h² = 0.61, respectively. In multivariate analysis, no significant genetic correlations among factors were found. These results suggest that heredity explains a substantial proportion of the variability of the factors that underlie the insulin resistance syndrome in American Indians and that these factors are genetically independent.     

Molecular models of NS3 protease variants of the Hepatitis C virus

Background  

Hepatitis C virus (HCV) currently infects approximately three percent of the world population. In view of the lack of vaccines against HCV, there is an urgent need for an efficient treatment of the disease by an effective antiviral drug. Rational drug design has not been the primary way for discovering major therapeutics. Nevertheless, there are reports of success in the development of inhibitor using a structure-based approach. One of the possible targets for drug development against HCV is the NS3 protease variants. Based on the three-dimensional structure of these variants we expect to identify new NS3 protease inhibitors. In order to speed up the modeling process all NS3 protease variant models were generated in a Beowulf cluster. The potential of the structural bioinformatics for development of new antiviral drugs is discussed.     

Study of response of Swiss Webster mice to light subunit of mushroom tyrosinase

The light subunit of mushroom, Agaricus bisporus, tyrosinase (LSMT), has been identified as an extrinsic component of the enzyme. Its function is unknown, but it can cross an epithelial cell layer, which suggests that it can be absorbed by the intestine. A similar capability has been demonstrated for the HA-33 component of the progenitor toxin from Clostridium botulinum, which is the closest structural homolog of LSMT. Unlike HA-33, LSMT appears to be non-immunogenic as shown by preliminary tests in Swiss Webster mice. We investigated the immunogenicity and histopathology of LSMT in mice to determine its safety in vivo. LSMT did not evoke generation of antibodies after prolonged periods of intraperitoneal administration. Histopathological observations confirmed the absence of responses in organs after twelve weekly administrations of LSMT. We found that LSMT is not toxic and is less immunogenic than the C. botulinum HA-33 protein, which supports further research and development for pharmaceutical application.     

A Dutch guideline for the treatment of scoliosis in neuromuscular disorders

Background

Children with neuromuscular disorders with a progressive muscle weakness such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy frequently develop a progressive scoliosis. A severe scoliosis compromises respiratory function and makes sitting more difficult. Spinal surgery is considered the primary treatment option for correcting severe scoliosis in neuromuscular disorders. Surgery in this population requires a multidisciplinary approach, careful planning, dedicated surgical procedures, and specialized after care.

Methods

The guideline is based on scientific evidence and expert opinions. A multidisciplinary working group representing experts from all relevant specialties performed the research. A literature search was conducted to collect scientific evidence in answer to specific questions posed by the working group. Literature was classified according to the level of evidence.

Results

For most aspects of the treatment scientific evidence is scarce and only low level cohort studies were found. Nevertheless, a high degree of consensus was reached about the management of patients with scoliosis in neuromuscular disorders. This was translated into a set of recommendations, which are now officially accepted as a general guideline in the Netherlands.

Conclusion

In order to optimize the treatment for scoliosis in neuromuscular disorders a Dutch guideline has been composed. This evidence-based, multidisciplinary guideline addresses conservative treatment, the preoperative, perioperative, and postoperative care of scoliosis in neuromuscular disorders.     

Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies

A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a "cosmopolitan" tagging approach to capture the genetic diversity across approximately 2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.     

Mesencephalic dopaminergic neurons express a repertoire of olfactory receptors and respond to odorant-like molecules

Background

The mesencephalic dopaminergic (mDA) cell system is composed of two major groups of projecting cells in the Substantia Nigra (SN) (A9 neurons) and the Ventral Tegmental Area (VTA) (A10 cells). Selective degeneration of A9 neurons occurs in Parkinson’s disease (PD) while abnormal function of A10 cells has been linked to schizophrenia, attention deficit and addiction. The molecular basis that underlies selective vulnerability of A9 and A10 neurons is presently unknown.

Results

By taking advantage of transgenic labeling, laser capture microdissection coupled to nano Cap-Analysis of Gene Expression (nanoCAGE) technology on isolated A9 and A10 cells, we found that a subset of Olfactory Receptors (OR)s is expressed in mDA neurons. Gene expression analysis was integrated with the FANTOM5 Helicos CAGE sequencing datasets, showing the presence of these ORs in selected tissues and brain areas outside of the olfactory epithelium. OR expression in the mesencephalon was validated by RT-PCR and in situ hybridization. By screening 16 potential ligands on 5 mDA ORs recombinantly expressed in an heterologous in vitro system, we identified carvone enantiomers as agonists at Olfr287 and able to evoke an intracellular Ca²⁺ increase in solitary mDA neurons. ORs were found expressed in human SN and down-regulated in PD post mortem brains.

Conclusions

Our study indicates that mDA neurons express ORs and respond to odor-like molecules providing new opportunities for pharmacological intervention in disease.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-729) contains supplementary material, which is available to authorized users.     

In vitro assessment of some sperm function following exposure to levonorgestrel in human fallopian tubes

Background  

The mechanism of action of levonorgestrel (LNG) as emergency contraception (EC) remains a subject of debate and its effect on sperm function has been only partially explained. The aim of this study was to assess whether LNG at a similar dose to those found in serum following oral intake for EC could affect spermatozoa when exposed to human fallopian tubes in vitro.     

Genetic Variability of Adult Body Mass Index: A Longitudinal Assessment in Framingham Families

Objective: To explore the contribution of genetics to the mean, SD, maximum value, maximum less the mean, and change over time in body mass index (BMI) and the residual of body weight after adjustment for height. BMI is frequently used as a general indicator of obesity because of its ease and reliability in ascertainment. Cross‐sectional twin and family studies have shown a moderate‐to‐substantial genetic component for BMI. However, the contribution of genetics to the long‐term average, variability, or change over time in BMI is less clear. Research Methods and Procedures: Longitudinal data from the Framingham heart study were used to create pedigrees of age‐matched individuals. Heritability estimates were derived using variance‐decomposition methods on a total of 1051 individuals from 380 extended pedigrees followed for a period of 20 years. All subjects were followed from approximately age 35 to 55 years. Results: Moderate heritability estimates were found for the mean BMI (h² = 0.37), maximum BMI (h² = 0.40), and the mean residual of body weight (h² = 0.36). Low heritability estimates (h² ? 0.20) were found for the maximum less the mean in BMI and the SDs of BMI and residual of body weight. No additive genetic contribution was found for the average change over time in BMI or the residual of body weight. Discussion: These findings suggest that there is a significant genetic component for the magnitude of BMI throughout an individual's middle‐adult years; however, little evidence was found for a genetic contribution to the variability or rate of change in an individual's BMI.     

Sex-specific interaction between APOE genotype and carbohydrate intake affects plasma HDL-C levels: the Strong Heart Family Study

Low plasma levels of high-density lipoprotein cholesterol (HDL-C) are identified as a risk factor for cardiovascular disease (CVD). Sexual dimorphism, however, is widely reported in both HDL-C and CVD, with the underlying explanations of these sexual differences not fully understood. HDL-C is a complex trait influenced by both genes and dietary factors. Here we examine evidence for a sex-specific effect of APOE and the macronutrient carbohydrate on HDL-C, triglycerides (TG) and apoprotein A-1 (ApoA-1) in a sample of 326 male and 423 female participants of the Strong Heart Family Study (SHFS). Using general estimating equations in SAS to account for kinship correlations, stratifying by sex, and adjusting for age, body mass index (BMI) and SHS center, we examine the relationship between APOE genotype and carbohydrate intake on circulating levels of HDL-C, TG, and ApoA-1 through a series of carbohydrate-by-sex interactions and stratified analyses. APOE-by-carbohydrate intake shows significant sex-specific effects. All males had similar decreases in HDL-C levels associated with increased carbohydrate intake. However, only those females with APOE-4 alleles showed significantly lower HDL-C levels as their percent of carbohydrate intake increased, while no association was noted between carbohydrate intake and HDL-C in those females without an APOE-4 allele. These findings demonstrate the importance of understanding sex differences in gene-by-nutrient interaction when examining the complex architecture of HDL-C variation.