Shared genetic contribution of type 2 diabetes and cardiovascular disease: Implications for prognosis and treatment

Purpose of Review: The increased cardiovascular disease (CVD) risk in subjects with type 2 diabetes (T2D) is well established. This review collates the available evidence and assesses the shared genetic background between T2D and CVD: the causal contribution of common risk factors to T2D and CVD and how genetics can be used to improve drug development and clinical outcomes. Recent Findings: Large-scale genome-wide association studies (GWAS) of T2D and CVD support a shared genetic background but minimal individual locus overlap. Summary: Mendelian randomisation (MR) analyses show that T2D is causal for CVD, but GWAS of CVD, T2D and their common risk factors provided limited evidence for individual locus overlap. Distinct but functionally related pathways were enriched for CVD and T2D genetic associations reflecting the lack of locus overlap and providing some explanation for the variable associations of common risk factors with CVD and T2D from MR analyses

forsan et haec olim meminisse iuvabit

Title from PDF of title page viewed June 20, 2018Thesis advisor: Chen YiVitaThesis (M.M.)--Conservatory of Music and Dance. University of Missouri--Kansas City, 2018This quartet features a transparent structure in which a dense, static ensemble motif gradually and smoothly transforms into a highly active and agitated counter-motif. This process repeats twice: with each iteration, the motif and counter-motif return in subtler, brighter forms as their texture and timbers evolve, as the quartet seems to recall the preceding material in decreasingly vivid manifestation. These motifs and the developmental climaxes invoke an organic sensation of breathing, both gentle shallow breaths and intense hyperventilation. Throughout, the quartet is asked to explore gradual transformations of playing techniques including bowing, vibrato and harmonics, as well as dramatic contrasts in texture and timber that emerge over the duration of the structure. In Book One of the Aeneid, as the titular hero and his crew are washed ashore and contemplating the harrows of their journey, Aeneas entreats his companions to stay resolute in their search for a New Troy, offering the hope that despite their challenges and suffering, “perhaps one day it will help to remember even these things.” Fundamentally, via organic contours and gradual evolutions, this quartet explores notions of remembrance and teleological determination.Abstract -- Performance notes -- Acknowledgements -- forsan et haec olim meminisse iuvabit -- vit

FAM13A and POM121C are candidate genes for fasting insulin: functional follow-up analysis of a genome-wide association study

Aims/hypothesis: By genome-wide association meta-analysis, 17 genetic loci associated with fasting serum insulin (FSI), a marker of systemic insulin resistance, have been identified. To define potential culprit genes in these loci, in a cross-sectional study we analysed white adipose tissue (WAT) expression of 120 genes in these loci in relation to systemic and adipose tissue variables, and functionally evaluated genes demonstrating genotype-specific expression in WAT (eQTLs). Methods: Abdominal subcutaneous adipose tissue biopsies were obtained from 114 women. Basal lipolytic activity was measured as glycerol release from adipose tissue explants. Adipocytes were isolated and insulin-stimulated incorporation of radiolabelled glucose into lipids was used to quantify adipocyte insulin sensitivity. Small interfering RNA-mediated knockout in human mesenchymal stem cells was used for functional evaluation of genes. Results: Adipose expression of 48 of the studied candidate genes associated significantly with FSI, whereas expression of 24, 17 and 2 genes, respectively, associated with adipocyte insulin sensitivity, lipolysis and/or WAT morphology (i.e. fat cell size relative to total body fat mass). Four genetic loci contained eQTLs. In one chromosome 4 locus (rs3822072), the FSI-increasing allele associated with lower FAM13A expression and FAM13A expression associated with a beneficial metabolic profile including decreased WAT lipolysis (regression coefficient, R = −0.50, p = 5.6 × 10−7). Knockdown of FAM13A increased lipolysis by ~1.5- fold and the expression of LIPE (encoding hormone-sensitive lipase, a rate-limiting enzyme in lipolysis). At the chromosome 7 locus (rs1167800), the FSI-increasing allele associated with lower POM121C expression. Consistent with an insulin-sensitising function, POM121C expression associated with systemic insulin sensitivity (R = −0.22, p = 2.0 × 10−2), adipocyte insulin sensitivity (R = 0.28, p = 3.4 × 10−3) and adipose hyperplasia (R = −0.29, p = 2.6 × 10−2). POM121C knockdown decreased expression of all adipocyte-specific markers by 25–50%, suggesting that POM121C is necessary for adipogenesis. Conclusions/interpretation: Gene expression and adipocyte functional studies support the notion that FAM13A and POM121C control adipocyte lipolysis and adipogenesis, respectively, and might thereby be involved in genetic control of systemic insulin sensitivity

Effects of genetic loci associated with central obesity on adipocyte lipolysis

Objectives: Numerous genetic loci have been associated with measures of central fat accumulation, such as waist-to-hip ratio adjusted for body mass index (WHRadjBMI). However the mechanisms by which genetic variations influence obesity remain largely elusive. Lipolysis is a key process for regulation of lipid storage in adipocytes, thus is implicated in obesity and its metabolic complications. Here, genetic variants at 36 WHRadjBMI-associated loci were examined for their influence on abdominal subcutaneous adipocyte lipolysis. Subjects and Methods: Fasting subcutaneous adipose tissue biopsies were collected from 789 volunteers (587 women and 202 men, body mass index (BMI) range 17.7–62.3 kg/m2). We quantified subcutaneous adipocyte lipolysis, both spontaneous and stimulated by the catecholamine isoprenaline or a cyclic AMP analogue. DNA was extracted from peripheral blood mononuclear cells and genotyping of SNPs associated with WHRadjBMI conducted. The effects on adipocyte lipolysis measures were assessed for SNPs individually and combined in a SNP score. Results: The WHRadjBMI-associated loci CMIP, PLXND1, VEGFA and ZNRF3-KREMEN1 demonstrated nominal associations with spontaneous and/or stimulated lipolysis. Candidate genes in these loci have been reported to influence NFκB-signaling, fat cell size and Wnt signalling, all of which may influence lipolysis. Significance: This report provides evidence for specific WHRadjBMI-associated loci as candidates to modulate adipocyte lipolysis. Additionally, our data suggests that genetically increased central fat accumulation is unlikely to be a major cause of altered lipolysis in abdominal adipocytes

Interaction of a heterodimerization partner with glucocorticoid receptor (GR), androgen receptor (AR) and GR/AR hybrids

Abstract only availableSteroid hormones are a class of compounds that play a role in regulating many functions. Glucocorticoid hormone is a compound in this class, which helps maintain homeostasis, including regulation of production of γ-fibrinogen, a protein that plays a major role in blood clotting. Glucocorticoid hormone acts by binding to an intracellular receptor protein called the glucocorticoid receptor (GR). GR bound to glucocorticoid then moves to the nucleus, where it interacts with another protein, Xenopus Glucocorticoid Receptor Accessory Factor (XGRAF), to form a heterodimer. This heterodimer binds to an upstream regulatory region of the DNA coding for the γ-fibrinogen gene that is composed of a binding site for XGRAF adjacent to a half GR recognition site (a classical GR response element consists of two elements). Binding of this heterodimer to the recognition sites regulates transcription of the γ-fibrinogen gene. The dimerization interaction relies on specific amino acid sequences on both proteins. These experiments will examine the amino acids on GR that are involved in heterodimerization with XGRAF. Androgen receptor (AR), is very similar to GR, so examining the differences in binding in the presence of XGRAF due to the substitutions could help determine what regions of GR are essential to XGRAF binding. To study the heterodimerization, several constructs that incorporate AR at different parts of GR in place of the normal sequence were expressed in a bacterial system and then isolated for analysis. The proteins were used in gel mobility shift assays which allow detection of the interaction between the nuclear receptors and XGRAF. After studying the binding of these constructs we have determined that the parts of AR that were substituted for GR still allow heterodimerization with XGRAF. Since both GR and AR have the ability to interact with XGRAF, we can speculate that similar types of heterodimerization mechanisms for nuclear receptors could be more common than previously thought.Life Sciences Undergraduate Research Opportunity Progra

Genome-wide association study of diabetogenic adipose morphology in the GENetics of Adipocyte Lipolysis (GENiAL) Cohort

An increased adipocyte size relative to the size of fat depots, also denoted hypertrophic adipose morphology, is a strong risk factor for the future development of insulin resistance and type 2 diabetes. The regulation of adipose morphology is poorly understood. We set out to identify genetic loci associated with adipose morphology and functionally evaluate candidate genes for impact on adipocyte development. We performed a genome-wide association study (GWAS) in the unique GENetics of Adipocyte Lipolysis (GENiAL) cohort comprising 948 participants who have undergone abdominal subcutaneous adipose biopsy with a determination of average adipose volume and morphology. The GWAS identified 31 genetic loci displaying suggestive association with adipose morphology. Functional evaluation of candidate genes by small interfering RNAs (siRNA)-mediated knockdown in adipose-derived precursor cells identified six genes controlling adipocyte renewal and differentiation, and thus of potential importance for adipose hypertrophy. In conclusion, genetic and functional studies implicate a regulatory role for ATL2, ARHGEF10, CYP1B1, TMEM200A, C17orf51, and L3MBTL3 in adipose morphology by their impact on adipogenesis

MUC1 as a Putative Prognostic Marker for Prostate Cancer

MUC1 is expressed on the apical surface of glandular epithelium. With functions including protection, adhesion and signaling, MUC1 has been implicated in prostate cancer. There are many splice variants, the best characterized of which are MUC1/1 and MUC1/2 which are determined by a SNP (rs4072037, 3506G>A)

Fuel Management in Large Pressurized Water Reactors

Economic and operational ground rules and their effects on fuel management are summarized, and examples showing the approach to typical fuel management problems are presented. The problems associated with in-core fuel management are also discussed, and the merits of various fuel cycling methods are evaluated. (D.C.W.

The association between C-reactive protein, mood disorder, and cognitive function in UK Biobank

Background: Systemic inflammation has been linked with mood disorder and cognitive impairment. The extent of this relationship remains uncertain, with the effects of serum inflammatory biomarkers compared to genetic predisposition toward inflammation yet to be clearly established. Methods: We investigated the magnitude of associations between C-reactive protein (CRP) measures, lifetime history of bipolar disorder or major depression, and cognitive function (reaction time and visuospatial memory) in 84,268 UK Biobank participants. CRP was measured in serum and a polygenic risk score for CRP was calculated, based on a published genome-wide association study. Multiple regression models adjusted for sociodemographic and clinical confounders. Results: Increased serum CRP was significantly associated with mood disorder history (Kruskal–Wallis H = 196.06, p < 0.001, η2 = 0.002) but increased polygenic risk for CRP was not (F = 0.668, p = 0.648, η2 < 0.001). Compared to the lowest quintile, the highest serum CRP quintile was significantly associated with both negative and positive differences in cognitive performance (fully adjusted models: reaction time B = −0.030, 95% CI = −0.052, −0.008; visuospatial memory B = 0.066, 95% CI = 0.042, 0.089). More severe mood disorder categories were significantly associated with worse cognitive performance and this was not moderated by serum or genetic CRP level. Conclusions: In this large cohort study, we found that measured inflammation was associated with mood disorder history, but genetic predisposition to inflammation was not. The association between mood disorder and worse cognitive performance was very small and did not vary by CRP level. The inconsistent relationship between CRP measures and cognitive performance warrants further study