Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits

Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.Peer reviewe

Identification of seven novel loci associated with amino acid levels using single-variant and gene-based tests in 8545 Finnish men from the METSIM study

Comprehensivemetabolite profiling capturesmany highly heritable traits, including amino acid levels, which are potentially sensitive biomarkers for disease pathogenesis. To better understand the contribution of genetic variation to amino acid levels, we performed single variant and gene-based tests of association between nine serumamino acids (alanine, glutamine, glycine, histidine, isoleucine, leucine, phenylalanine, tyrosine, and valine) and 16.6million genotyped and imputed variants in 8545 nondiabetic Finnishmen fromtheMETabolic Syndrome In Men (METSIM) study with replication in Northern Finland Birth Cohort (NFBC1966).We identified five novel loci associated with amino acid levels (P = &lt; 5×10-8): LOC157273/PPP1R3B with glycine (rs9987289, P = 2.3×10-26); ZFHX3 (chr16:73326579,minor allele frequency (MAF) = 0.42%, P = 3.6×10-9), LIPC (rs10468017, P = 1.5×10-8), and WWOX (rs9937914, P = 3.8×10-8) with alanine; and TRIB1 with tyrosine (rs28601761, P = 8×10-9). Gene-based tests identified two novel genes harboringmissense variants ofMAF &lt; 1% that show aggregate association with amino acid levels: PYCR1 with glycine (Pgene = 1.5×10-6) and BCAT2 with valine (Pgene = 7.4×10-7); neither gene was implicated by single variant association tests. These findings are among the first applications of gene-based tests to identify new loci for amino acid levels. In addition to the seven novel gene associations, we identified five independent signals at established amino acid loci, including two rare variant signals at GLDC (rs138640017,MAF=0.95%, Pconditional = 5.8×10-40) with glycine levels and HAL (rs141635447,MAF = 0.46%, Pconditional = 9.4×10-11) with histidine levels. Examination of all single variant association results in our data revealed a strong inverse relationship between effect size and MAF (Ptrend &lt; 0.001). These novel signals provide further insight into the molecularmechanisms of amino acidmetabolismand potentially, their perturbations in disease

A busca por um marco processual da internet : requisitos para colheita dos dados armazenados em compartimentos eletr?nicos

Submitted by PPG Ci?ncias Criminais ([email protected]) on 2018-07-11T18:42:24Z No. of bitstreams: 1 Disserta??o_Ivan Jezler Costa J?nior_vers?o dep?sito biblioteca PUCRS_08_06_2018_com capa e contracapa.pdf: 2153899 bytes, checksum: 22b1ffc03b820d4e1b4f17b19739ea18 (MD5)Approved for entry into archive by Sheila Dias ([email protected]) on 2018-07-16T13:19:03Z (GMT) No. of bitstreams: 1 Disserta??o_Ivan Jezler Costa J?nior_vers?o dep?sito biblioteca PUCRS_08_06_2018_com capa e contracapa.pdf: 2153899 bytes, checksum: 22b1ffc03b820d4e1b4f17b19739ea18 (MD5)Made available in DSpace on 2018-07-16T13:27:26Z (GMT). No. of bitstreams: 1 Disserta??o_Ivan Jezler Costa J?nior_vers?o dep?sito biblioteca PUCRS_08_06_2018_com capa e contracapa.pdf: 2153899 bytes, checksum: 22b1ffc03b820d4e1b4f17b19739ea18 (MD5) Previous issue date: 2018-03-22This paper analyzes the Civil Internet Framework in the context of the right to evidence in criminal proceedings. From the new technological resources of investigation energized by electronic compartments and by the Internet, the main legislative vacuums were pointed out in the orientation of these means of proof. There are no strong guiding rules, which contributed to a jurisprudential oscillation, with arbitrariness and decisionism in judicial decisions analyzed. In the pursuit of an absolute and anticipated truth, the trivialization of the hidden means of investigation had been demonstrated, even directly, when a public audience had been witnessed and concluded, which pursued the insertion of back door in applications with rigid encryption to propitiate the collection of communications stored in these telematic vehicles. The criminal prosecution organs questioned on this solemnity still supported the suppression of the rules of international cooperation for the collection of electronic data abroad. The distinction between interception and capture of conversations had still been drawn in a watertight manner. The general objective of the research is to analyze if the Civil Framework of the Internet presents itself as sufficient to regulate the capture of telematic data stored in electronic compartments. For that, a critical and multidisciplinary analysis of the themes was done, based on the consultation of scientific works and journalistic publications, and the documentary research was used to demonstrate the need to face the theme and the practical relevance of the theme, as attested by the analysis of the decisions of the Superior Courts and manifestations of other procedural subjects. As a result, the necessity of a proper legal regime for the search of digital data stored in electronic compartments was evidenced. The devices that regulate orthodox search and seizure do not have the ability to maintain the integrity and sameness of content volatile, tangible, and easily deteriorated. At the same time, in the wake of what had been commented on the ontological distinction between interception and informational search, the rule of Law no. 9,296, dated July 24, 1996, can not preserve the specificities of the collection of stored content. In this step, the application of the extensive and privileged interpretation, a taxation with protection in a constitutional hermeneutic, had been removed. It is concluded that the Civilian Internet Framework did not provide, with requirements and assumptions, the blind spot mentioned. There are no clear rules as to legitimacy, competence, reasoning and timing. This void provided the analysis of decisions of the first degree to the Federal Supreme Court, which evidenced the legal insecurity built by a non-existent or deficient legislation.Este trabalho analisa o Marco Civil da Internet no contexto do direito ? prova no processo penal. A partir dos novos recursos tecnol?gicos de investiga??o energizados por compartimentos eletr?nicos e pela Internet, elencaram-se os principais v?cuos legislativos na orienta??o desses meios de prova. N?o h? regras orientadoras fortes, o que contribuiu para uma oscila??o jurisprudencial, com arbitrariedade e decisionismo em decis?es jurisdicionais analisadas. Na busca de uma verdade absoluta e antecipada, a banaliza??o dos meios ocultos de investiga??o fora demonstrada, inclusive diretamente, quando se presenciou e se colocou, a termo, uma audi?ncia p?blica que perseguiu a inser??o de porta dos fundos em aplicativos com criptografia r?gida para propiciar a coleta de comunica??es armazenadas nesses ve?culos telem?ticos. Os ?rg?os de persecu??o penal inquiridos nessa solenidade ainda sustentaram a supress?o das regras de coopera??o internacional para a coleta de dados eletr?nicos no exterior. Ainda fora tra?ada a distin??o entre intercepta??o e capta??o das conversas de maneira estanque. O objetivo geral da pesquisa busca analisar se o Marco Civil da Internet se apresenta como suficiente para regrar a capta??o de dados telem?ticos armazenados em compartimentos eletr?nicos. Para tanto, foi realizada uma an?lise cr?tica e multidisciplinar dos temas, a partir da consulta a trabalhos cient?ficos e publica??es jornal?sticas, sendo cogente a pesquisa documental para demonstrar a necessidade de enfrentamento do tema e a relev?ncia pr?tica do mesmo, como ficou atestado pela an?lise das decis?es dos Tribunais Superiores e manifesta??es de outros sujeitos processuais. Como resultado, evidenciou-se a necessidade de um regime jur?dico pr?prio para a busca de dados digitais armazenados em compartimentos eletr?nicos. Os dispositivos que regram a busca e apreens?o ortodoxa n?o t?m o cond?o de manter a integridade e mesmidade de conte?do vol?til, tang?vel e com f?cil deteriora??o. Ao mesmo tempo, na esteira do que fora comentado sobre a distin??o ontol?gica entre intercepta??o e busca informacional, o regramento da Lei n. 9.296, de 24 de julho de 1996, n?o pode preservar as especificidades da coleta de conte?do armazenado. Nesse passo, fora afastada a aplica??o da interpreta??o extensiva e privilegiada, uma taxatividade com amparo em uma hermen?utica constitucional. Conclui-se que o Marco Civil da Internet n?o supriu, com requisitos e pressupostos, o ponto cego mencionado. N?o h? regras claras quanto ? legitimidade, compet?ncia, fundamenta??o e prazo. Esse vazio proporcionou a an?lise de decis?es do primeiro grau ao Supremo Tribunal Federal, o que evidenciou a inseguran?a jur?dica constru?da por uma legisla??o inexistente ou deficiente

A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at &gt;400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate &lt;0.05 (corresponding P = 6.9 x 10(-6)) with replication at Bonferroni-corrected P &lt; 8.6 x 10(-4). Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 x 10(-4)). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups

Population genetic differentiation of height and body mass index across Europe

Across-nation differences in the mean values for complex traits are common, but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24% (95% credible interval (CI) = 9%, 41%) and 8% (95% CI = 4%, 16%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 × 10 -8; BMI, P < 5.95 × 10 -4), and we find an among-population genetic correlation for tall and slender individuals (r = -0.80, 95% CI = -0.95, -0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58)

Aurora B Kinase Exists in a Complex with Survivin and INCENP and Its Kinase Activity Is Stimulated by Survivin Binding and Phosphorylation

Aurora B regulates chromosome segregation and cytokinesis and is the first protein to be implicated as a regulator of bipolar attachment of spindle microtubules to kinetochores. Evidence from several systems suggests that Aurora B is physically associated with inner centromere protein (INCENP) in mitosis and has genetic interactions with Survivin. It is unclear whether the Aurora B and INCENP interaction is cell cycle regulated and if Survivin physically interacts in this complex. In this study, we cloned the Xenopus Survivin gene, examined its association with Aurora B and INCENP, and determined the effect of its binding on Aurora B kinase activity. We demonstrate that in the Xenopus early embryo, all of the detectable Survivin is in a complex with both Aurora B and INCENP throughout the cell cycle. Survivin and Aurora B bind different domains on INCENP. Aurora B activity is stimulated >10-fold in mitotic extracts; this activation is phosphatase sensitive, and the binding of Survivin is required for full Aurora B activity. We also find the hydrodynamic properties of the Aurora B/Survivin/INCENP complex are cell cycle regulated. Our data indicate that Aurora B kinase activity is regulated by both Survivin binding and cell cycle-dependent phosphorylation