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

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

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

Civil Drone Ethics and Sustainability

In order to solve the largely ignored issues of civil drones it is imperative to develop a framework that assures an ethical and sustainable practice. This paper analyses continuing ethical and sustainable issues, then reviews existing literature focused on these issues and their recommended solutions. Highlighted while reviewing literature was the common shortcoming of not considering that sensors other than cameras can breach privacy. Furthermore, a revised code of ethics/sustainability is developed and divided into the following principles: flying zones, data acquisition, data processing, and sustainable practice. To evaluate the code of ethics/sustainability it was applied to a case study of inspecting a solar farm in New Zealand. The case study showed the code createda non-invasive and sustainable drone practice. Rapid civil drone development calls for further development of this paper and related studies

Knights, Puritans, and Jesus: Robert E. Lee, Jefferson Davis, Stonewall Jackson, and the archetypes of American masculinity

I interpret Civil War romanticism by looking at well-known archetypal characters such as the knight, the Puritan, and the Christ figure. I argue that sectional reunion occurred, in part, because Americans shared a common celebration of the Christian/chivalrous hero expressed through stories about the lives and personalities of leading figures of the Civil War. Western traditions like Christianity and its medieval warrior code, chivalry, conditioned Americans to seek heroes who conformed to a certain pattern that resembled the knightly ideal. Chivalry did not crowd-out other forms of masculine behavior, but during the nineteenth century, the British century, Americans had not yet created a man in their own image. That would come later with the twentieth century’s most favored man: the cowboy. Americans created Robert E. Lee as a knight figure resembling Western heroes such as King Arthur. Unlike the more controversial Confederate notables Stonewall Jackson and Jefferson Davis, the Lee figure offered Americans the genteel, Christ-like, hero who could be made to represent all of white America. Davis was too defiantly unreconstructed to ever affect much sectional agreement, and Jackson simply could not be made to fit the chivalrous pattern. Thus, Lee allowed southerners to identify themselves as uniquely chivalrous and honorable compared to the modern North. At the same time, the Lee figure provided northerners the opportunity to romanticize a charming, orderly, Old South while rejecting the violent, narrow-minded, states\u27 rights South best symbolized by Davis. I prefer to interpret commentary about the Civil War as storytelling and do not use terms such as the Lost Cause or Civil War memory. High-ranking officers, the common solider, and those who never participated in the Civil War each told stories about it. Due to the large number of stories told, certain common themes became evident in American interpretations of the Civil War era. Common stories include: Lee at Appomattox, Jackson\u27s unmerciful marches against Union forces, and Davis (almost) eluding capture dressed as a woman. Taken together the sub-stories reveal much about the grand narrative of the Civil War, and how Americans, though succeeding to a great extent, failed to completely reunite