Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10−33; LPA:p<10−19; 1p13.3:p<10−17) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10−7). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06–1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes

Analysis of amino acids essential for an interaction between glucocorticoid receptor and a heterdimerization partner [abstract]

Abstract only availableSteroid hormones of the glucocorticoid class regulate homeostasis, stress, the acute phase response, and several other functions. Specifically, glucocorticoid hormone is involved in regulation of ?-fibrinogen production, which plays a major role in blood clotting. Glucocorticoids act by binding to glucocorticoid receptor (GR), an intracellular receptor protein. Glucocorticoid binding enables GR to be transported to the nucleus, where GR binds to DNA, influencing gene expression. The classical DNA binding site for GR is a glucocorticoid response element (GRE) with the sequence 5? GGTACAnnnTGTTCT 3?. However, to regulate the ?-fibrinogen gene in frog liver cells, GR interacts with another protein, Xenopus Glucocorticoid Receptor Accessory Factor (XGRAF), to form a heterodimer. This complex binds to an upstream position on the ?-fibrinogen gene that possesses a non-classical recognition site, composed of an XGRAF binding site (italicized) adjacent to a downstream half GRE, 5? GAGTTAA TGTTCC 3?. It has been shown that heterodimer binding to this site increases transcription of the ?-fibrinogen gene in response to hormone treatment in liver cells. Formation of the XGRAF:GR complex is expected to rely on interactions between specific amino acids in both proteins. To examine which amino acids within GR are essential for that dimerization interaction, stretches of amino acids in GR have been substituted with analogous regions from other proteins in the steroid receptor/nuclear receptor family. A closely related protein, androgen receptor (AR), was the initial source of the amino acid sequences. The GR/AR hybrids were still able to heterodimerize with XGRAF. Based on those data, a more distantly related protein, called Daf-12, from the nematode C. elegans was chosen as the new amino acid sequence source. If complex formation with XGRAF is disrupted in the GR/Daf-12 hybrids, it would indicate that the specific amino acids on GR, substituted with Daf-12, may be involved in direct protein-protein interactions between GR and XGRAF.Life Sciences Undergraduate Research Opportunity Progra

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

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

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

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