A meta-analysis of gene expression signatures of blood pressure and hypertension

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%-9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension.Tianxiao Huan, Tõnu Esko, Marjolein J. Peters, Luke C. Pilling, Katharina Schramm, Claudia Schurmann, Brian H. Chen, Chunyu Liu, Roby Joehanes, Andrew D. Johnson, Chen Yao, Sai-xia Ying, Paul Courchesne, Lili Milani, Nalini Raghavachari, Richard Wang, Poching Liu, Eva Reinmaa, Abbas Dehghan, Albert Hofman, André G. Uitterlinden, Dena G. Hernandez, Stefania Bandinelli, Andrew Singleton, David Melzer, Andres Metspalu, Maren Carstensen, Harald Grallert, Christian Herder, Thomas Meitinger, Annette Peters, Michael Roden, Melanie Waldenberger, Marcus Dörr, Stephan B. Felix, Tanja Zeller, International Consortium for Blood Pressure GWAS, ICBP, Ramachandran Vasan, Christopher J. O'Donnell, Peter J. Munson, Xia Yang, Holger Prokisch, Uwe Völker, Joyce B. J. van Meurs, Luigi Ferrucci, Daniel Lev

Study on COgnition and Prognosis in the Elderly (SCOPE)

Blood Press. 1999;8(3):177-83. Study on COgnition and Prognosis in the Elderly (SCOPE). Hansson L, Lithell H, Skoog I, Baro F, Bánki CM, Breteler M, Carbonin PU, Castaigne A, Correia M, Degaute JP, Elmfeldt D, Engedal K, Farsang C, Ferro J, Hachinski V, Hofman A, James OF, Krisin E, Leeman M, de Leeuw PW, Leys D, Lobo A, Nordby G, Olofsson B, Zanchetti A, et al. University of Uppsala, Department of Public Health, Sweden. Abstract The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multicentre, prospective, randomized, double-blind, parallel-group study designed to compare the effects of candesartan cilexetil and placebo in elderly patients with mild hypertension. The primary objective of the study is to assess the effect of candesartan cilexetil on major cardiovascular events. The secondary objectives of the study are to assess the effect of candesartan cilexetil on cognitive function and on total mortality, cardiovascular mortality, myocardial infarction, stroke, renal function, hospitalization, quality of life and health economics. Male and female patients aged between 70 and 89 years, with a sitting systolic blood pressure (SBP) of 160-179 mmHg and/or diastolic blood pressure (DBP) of 90-99 mmHg, and a Mini-Mental State Examination (MMSE) score of 24 or above, are eligible for the study. The overall target study population is 4000 patients, at least 1000 of whom are also to be assessed for quality of life and health economics data. After an open run-in period lasting 1-3 months, during which patients are assessed for eligibility and those who are already on antihypertensive therapy at enrolment are switched to hydrochlorothiazide 12.5 mg o.d., patients are randomized to receive either candesartan cilexetil 8 mg once daily (o.d.) or matching placebo o.d. At subsequent study visits, if SBP remains >160 mmHg, or has decreased by 85 mmHg, study treatment is doubled to candesartan cilexetil 16 mg o.d. or two placebo tablets o.d. Recruitment was completed in January 1999. At that time 4964 patients had been randomized. All randomized patients will be followed for an additional 2 years. If the event rate is lower than anticipated, the follow-up will be prolonged. PMID: 10595696 [PubMed - indexed for MEDLINE

Kerr/CFT, dipole theories and nonrelativistic CFTs

We study solutions of type IIB supergravity which are SL(2,R) x SU(2) x U(1)^2 invariant deformations of AdS_3 x S^3 x K3 and take the form of products of self-dual spacelike warped AdS_3 and a deformed three-sphere. One of these backgrounds has been recently argued to be relevant for a derivation of Kerr/CFT from string theory, whereas the remaining ones are holographic duals of two-dimensional dipole theories and their S-duals. We show that each of these backgrounds is holographically dual to a deformation of the DLCQ of the D1-D5 CFT by a specific supersymmetric (1,2) operator, which we write down explicitly in terms of twist operators at the free orbifold point. The deforming operator is argued to be exactly marginal with respect to the zero-dimensional nonrelativistic conformal (or Schroedinger) group - which is simply SL(2,R)_L x U(1)_R. Moreover, in the supergravity limit of large N and strong coupling, no other single-trace operators are turned on. We thus propose that the field theory duals to the backgrounds of interest are nonrelativistic CFTs defined by adding the single Schroedinger-invariant (1,2) operator mentioned above to the original CFT action. Our analysis indicates that the rotating extremal black holes we study are best thought of as finite right-moving temperature (non-supersymmetric) states in the above-defined supersymmetric nonrelativistic CFT and hints towards a more general connection between Kerr/CFT and two-dimensional non-relativistic CFTs.Comment: 48+8 pages, 4 figures; minor corrections and references adde

Efficient Physical Embedding of Topologically Complex Information Processing Networks in Brains and Computer Circuits

Nervous systems are information processing networks that evolved by natural selection, whereas very large scale integrated (VLSI) computer circuits have evolved by commercially driven technology development. Here we follow historic intuition that all physical information processing systems will share key organizational properties, such as modularity, that generally confer adaptivity of function. It has long been observed that modular VLSI circuits demonstrate an isometric scaling relationship between the number of processing elements and the number of connections, known as Rent's rule, which is related to the dimensionality of the circuit's interconnect topology and its logical capacity. We show that human brain structural networks, and the nervous system of the nematode C. elegans, also obey Rent's rule, and exhibit some degree of hierarchical modularity. We further show that the estimated Rent exponent of human brain networks, derived from MRI data, can explain the allometric scaling relations between gray and white matter volumes across a wide range of mammalian species, again suggesting that these principles of nervous system design are highly conserved. For each of these fractal modular networks, the dimensionality of the interconnect topology was greater than the 2 or 3 Euclidean dimensions of the space in which it was embedded. This relatively high complexity entailed extra cost in physical wiring: although all networks were economically or cost-efficiently wired they did not strictly minimize wiring costs. Artificial and biological information processing systems both may evolve to optimize a trade-off between physical cost and topological complexity, resulting in the emergence of homologous principles of economical, fractal and modular design across many different kinds of nervous and computational networks

Meta-Analysis of Genome-Wide Scans for Human Adult Stature Identifies Novel Loci and Associations with Measures of Skeletal Frame Size

Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GW-significant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1×10−8 and rs910316 in TMED10, P-value = 1.4×10−7) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3×10−7 and rs849141 in JAZF1, P-value = 3.2×10−11). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4×10−5 and rs6817306 in LCORL, P-value = 4×10−4), hip axis length (including rs6830062 at LCORL, P-value = 4.8×10−4 and rs4911494 at UQCC, P-value = 1.9×10−4), and femur length (including rs710841 at PRKG2, P-value = 2.4×10−5 and rs10946808 at HIST1H1D, P-value = 6.4×10−6). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height

The social production of substance abuse and HIV/HCV risk: an exploratory study of opioid-using immigrants from the former Soviet Union living in New York City

<p>Abstract</p> <p>Background</p> <p>Several former Soviet countries have witnessed the rapid emergence of major epidemics of injection drug use (IDU) and associated HIV/HCV, suggesting that immigrants from the former Soviet Union (FSU) may be at heightened risk for similar problems. This exploratory study examines substance use patterns among the understudied population of opioid-using FSU immigrants in the U.S., as well as social contextual factors that may increase these immigrants' susceptibility to opioid abuse and HIV/HCV infection.</p> <p>Methods</p> <p>In-depth interviews were conducted with 10 FSU immigrants living in New York City who initiated opioid use in adolescence or young adulthood, and with 6 drug treatment providers working with this population. Informed by a grounded theory approach, interview transcripts were inductively coded and analyzed to identify key themes.</p> <p>Results</p> <p>The "trauma" of the immigration/acculturation experience was emphasized by participants as playing a critical role in motivating opioid use. Interview data suggest that substance use patterns formed in the high-risk environment of the FSU may persist as behavioral norms within New York City FSU immigrant communities - including a predilection for heroin use among youth, a high prevalence of injection, and a tolerance for syringe sharing within substance-using peer networks. Multiple levels of social context may reproduce FSU immigrants' vulnerability to substance abuse and disease such as: peer-based interactional contexts in which participants typically used opioids; community workplace settings in which some participants were introduced to and obtained opioids; and cultural norms, with roots in Soviet-era social policies, stigmatizing substance abuse which may contribute to immigrants' reluctance to seek disease prevention and drug treatment services.</p> <p>Conclusion</p> <p>Several behavioral and contextual factors appear to increase FSU immigrants' risk for opioid abuse, IDU and infectious disease. Further research on opioid-using FSU immigrants is warranted and may help prevent increases in HIV/HCV prevalence from occurring within these communities.</p

Weekly Intra-Amniotic IGF-1 Treatment Increases Growth of Growth-Restricted Ovine Fetuses and Up-Regulates Placental Amino Acid Transporters

Frequent treatment of the growth-restricted (IUGR) ovine fetus with intra-amniotic IGF-1 increases fetal growth. We aimed to determine whether increased growth was maintained with an extended dosing interval and to examine possible mechanisms. Pregnant ewes were allocated to three groups: Control, and two IUGR groups (induced by placental embolization) treated with weekly intra-amniotic injections of either saline (IUGR) or 360 µg IGF-1 (IGF1). IUGR fetuses were hypoxic, hyperuremic, hypoglycemic, and grew more slowly than controls. Placental glucose uptake and SLC2A1 (GLUT2) mRNA levels decreased in IUGR fetuses, but SLC2A3 (GLUT3) and SLC2A4 (GLUT4) levels were unaffected. IGF-1 treatment increased fetal growth rate, did not alter uterine blood flow or placental glucose uptake, and increased placental SLC2A1 and SLC2A4 (but not SLC2A3) mRNA levels compared with saline-treated IUGR animals. Following IGF-1 treatment, placental mRNA levels of isoforms of the system A, y+, and L amino acid transporters increased 1.3 to 5.0 fold, while the ratio of phosphorylated-mTOR to total mTOR also tended to increase. Weekly intra-amniotic IGF-1 treatment provides a promising avenue for intra-uterine treatment of IUGR babies, and may act via increased fetal substrate supply, up-regulating placental transporters for neutral, cationic, and branched-chain amino acids, possibly via increased activation of the mTOR pathway

Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia

A Fermi Gamma-Ray Burst Monitor Search for Electromagnetic Signals Coincident with Gravitational-wave Candidates in Advanced LIGO's First Observing Run

We present a search for prompt gamma-ray counterparts to compact binary coalescence gravitational wave (GW) candidates from Advanced LIGO's first observing run (O1). As demonstrated by the multimessenger observations of GW170817/GRB 170817A, electromagnetic and GW observations provide complementary information about the astrophysical source, and in the case of weaker candidates, may strengthen the case for an astrophysical origin. Here we investigate low-significance GW candidates from the O1 compact binary coalescence searches using the Fermi Gamma-Ray Burst Monitor (GBM), leveraging its all sky and broad energy coverage. Candidates are ranked and compared to background to measure the significance. Those with false alarm rates (FARs) of less than 10−5 Hz (about one per day, yielding a total of 81 candidates) are used as the search sample for gamma-ray follow-up. No GW candidates were found to be coincident with gamma-ray transients independently identified by blind searches of the GBM data. In addition, GW candidate event times were followed up by a separate targeted search of GBM data. Among the resulting GBM events, the two with the lowest FARs were the gamma-ray transient GW150914-GBM presented in Connaughton et al. and a solar flare in chance coincidence with a GW candidate

GWAS for executive function and processing speed suggests involvement of the CADM2 gene

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.37