Low-density lipoproteins cause atherosclerotic cardiovascular disease : pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel

Peer reviewe

Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 ] HEALTH ]F2 ]2009 ]223175). The CIMBA data management and data analysis were supported by Cancer Research.UK grants 12292/A11174 and C1287/A10118. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME ]ON Post ]GWAS Initiative (U19 ]CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The cBio portal is developed and maintained by the Computational Biology Center at Memorial Sloan ] Kettering Cancer Center. SH is supported by an NHMRC Program Grant to GCT. Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium, funding for which was provided by the Wellcome Trust under award 076113. The results published here are, in part, based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancerhttp://dx.doi.org/10.1038/ng.3185This is the Author Accepted Manuscript of 'Identification of six new susceptibility loci for invasive epithelial ovarian cancer' which was published in Nature Genetics 47, 164–171 (2015) © Nature Publishing Group - content may only be used for academic research

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P<1.4 × 10−3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10−10 for risk variants (P<10−4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC

The role of locally expressed angiotensin converting enzyme in cardiac remodeling after myocardial infarction in mice

Angiotensin II, generated from angiotensin I by angiotensin converting enzyme (ACE), induces multiple effects including vasoconstriction, positive cardiac inotropy, hypertrophy of cardiomyocytes and proliferation of fibroblasts. ACE exists both in a tissue-bound (t-ACE) and a soluble form. The functional importance of locally produced angiotensin II is still unclear. In the present study, mice lacking tissue-bound angiotensin converting enzyme (t-ACE -/-) were used to investigate the importance of t-ACE during cardiac remodeling after myocardial infarction. Mice were subjected to coronary artery occlusion or sham surgery. At 14 days after MI, stroke volume (SV) was determined with an electromagnetic flow probe around the ascending aorta. Mean arterial pressure (MAP) was measured through a cannula in the abdominal aorta. Both parameters were determined at rest and after a volume loading of 2.5 ml warm (37 degrees C) Ringer's solution in 60 s. Hearts were dissected and formalin-fixed to measure infarct size, cardiac dimensions and collagen concentration. Tissue levels of angiotensin I and II were determined in hearts and kidneys. At rest, under pentobarbital anaesthesia, t-ACE -/- mice (n=12) exhibited a significantly lower MAP (26+/-3 vs. 45+/-3 mmHg) than t-ACE +/+ (n=11). SV was similar in both strains. Maximal SV was significantly reduced after MI. Furthermore, infarcted t-ACE -/- (n=6) exhibited a significantly lower maximal SV compared to infarcted t-ACE +/+ mice (n=5; 20.4+/-1.5 vs. 29.6+/-2.3 microl). Structural cardiac parameters as well as cardiac and renal angiotensin II levels in t-ACE -/- and t-ACE +/+ were comparable. These results suggest that the structural adaptations of the heart that follow MI are independent of t-ACE. However, the presence of t-ACE is necessary for maintenance of cardiac functio

Thermal and Photoluminescence Properties of Nd 3+ doped Tellurite Nanoglass

Abstract. Series of glasses based on (75-x)TeO 2 -15MgO-10Na 2 O-xNd 2 O 3 , where x=0, 1.0, 2.0 and 3.0, are synthesized by conventional melt-quenching technique. The nanoglass particles are derived from heat treatment of this glass near crystallisation temperature for 3 hours. The existence of nanocrystalline nature of this glass is confirmed by x-ray diffraction (XRD) technique followed by calculation using Scherrer equation. Meanwhile, the crystallization temperature, Tc determined using Differential thermal analysis (DTA). The fluorescence spectra of Nd 3+ ions exhibit emission transition of 2 P 3/2 → 4 I 9/2 , 4 G 7/2 → 4 I 9/2 , 2 H 11/2 → 4 I 9/2 , and 4 F 9/2 → 4 I 9/2 under 765 nm excitation wavelengths

Thermal and Photoluminescence Properties of Nd 3+ doped Tellurite Nanoglass

Abstract. Series of glasses based on (75-x)TeO 2 -15MgO-10Na 2 O-xNd 2 O 3 , where x=0, 1.0, 2.0 and 3.0, are synthesized by conventional melt-quenching technique. The nanoglass particles are derived from heat treatment of this glass near crystallisation temperature for 3 hours. The existence of nanocrystalline nature of this glass is confirmed by x-ray diffraction (XRD) technique followed by calculation using Scherrer equation. Meanwhile, the crystallization temperature, Tc determined using Differential thermal analysis (DTA). The fluorescence spectra of Nd 3+ ions exhibit emission transition of 2 P 3/2 → 4 I 9/2 , 4 G 7/2 → 4 I 9/2 , 2 H 11/2 → 4 I 9/2 , and 4 F 9/2 → 4 I 9/2 under 765 nm excitation wavelengths