Teses / dissertações sobre o tema "Association copy"

Master thesis, Master's degree program Marketing, Economic School Linnaeus University, Växjö Sweden, Spring semester 2015. Author: Andersson Anthon, Guntell Robin Tutor: Soniya Billore Examiner: Anders Pehrsson Title: Advancing the COO Construct From an Affective Dimension: The Application of Projective Technique Purpose: The purpose in this article is to break from traditional research and its accompanying cognitive research methods in order to advance the COO field from a more accurate perspective that also involves an affective dimension as well. Design/methodology/approach: Drawing from prior research in the COO field, the methodology accounted for assumptions that were tested in collage technique and ad copy technique. Findings: The results shows that some people only seems to be susceptible to COO influence when communicating emotional CSAs nonverbally, whilst some people only reveal rational CSAs when being cognitively asked about COO influence in a directed manner. As a result, the present findings might suggest that prior research in the academic field might suffer from bias. Practical implications: In the light of COO, managers should bear in mind that some people cannot be targeted with solely rely on a cognitive marketing communication strategy. More specifically, the ad copy technique provides guidelines for appropriate design of advertisements when one consider to serving the brand’s origin as salient cue in consumers’ minds. Originality/value: Advancing the COO construct with using collage technique, this study is to the best our knowledge the second to account for an affective dimension as well.

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RESUMO A presente tese apresenta os resultados da pesquisa de caráter predominantemente bibliográfico, cujo principal objetivo foi investigar as características formais e conceituais do futebol que tornassem possível afirmar que, na relação com o esporte em questão, o torcedor brasileiro vivencia uma verdadeira experiência trágica, conforme configurada nos termos poéticos, expressos a partir de elementos relacionados à sua forma, e nos termos teóricos, com base nos elementos relacionados a tal experiência do ponto de vista filosófico. Para tanto, foram investigados os diversos modos de compreensão do conceito de “tragédia” e de “trágico”, a partir da literatura dramática e da literatura filosófica que apresentam investigações sobre o tema, ancoradas, respectivamente, em Aristóteles e Friedrich Nietzsche. Além disso, foram construídos conceitos próprios e originais inspirados por uma lógica dramatúrgica, testados no objeto escolhido, qual seja, a Copa do Mundo de Futebol de 1950, realizada no Brasil, focando mais especificamente na última partida que foi disputada pelas seleções do Brasil e do Uruguai.
ABSTRACT This thesis presents the results of predominantly bibliographical research, which main objective was to investigate the formal and conceptual characteristics of football association (soccer) that would make possible to say that through the relationship with the sport in question, the Brazilian fan lives through a true tragic experience as configured in terms poetic expressed from elements related to its form, and a theoretically based on the information related to the experience from a philosophical point of view. Thereunto, different ways of understanding the concept of “tragedy” and “tragic” were investigated, from the dramatic literature and philosophical literature presenting research on the subject, anchored respectively in Aristotle and Friedrich Nietzsche. In addition, original and own concepts were built inspired by a dramaturgical logic tested in the chosen object, namely, the Football World Cup 1950, held in Brazil, focusing more specifically in the last match that was played between Brazilian’s and Uruguay’s teams.

Mestrado em Biomedicina Molecular
Chronic Obstructive Pulmonary Disease (COPD) is a multifactorial and heterogeneous disease which impacts differently on patients with similar grades. This suggests that factor others than lung function may affect patients experience of the disease. Patient-reported outcomes (PROs) are a set of measures that allow to assess patients’ self-perception and experience of the disease. Recent studies have reported associations between specific single nucleotide polymorphisms (SNPs) and PROs, however not much is known about these associations and their meanings. Thus, this study had as main objective to explore possible associations between specific genetic variants and clinical measures, including PROs. It also sought to contribute for a characterization of the genotypes from patients with COPD in Portugal. A cross-sectional study was conducted in a total number of 60 patients with COPD. The PROs assessed were: 1) self-reported frequency of exacerbations, 2) dyspnoea with modified Medical Research Council and Borg scales , 3) fatigue with Borg scale, 4) anxiety and depression with Hospital Anxiety and Depression scale; 5) impact of the disease with COPD Assessment Test and 6) health-related quality of life (HRQOL) with St. George Respiratory questionnaire; Additionally, several surrogate outcomes were also assessed i. e., lung function, peripheral muscle strength with digital dynamometer, respiratory muscle strength with the respiratory pressure assessment and functional capacity through the 1 minute and 5 time sit-to-stand. Both oropharyngeal swabs and saliva samples were collected from the patients for genotyping. Significant associations were found between genetic variants and dyspnoea (rs1143634, rs1042717, rs1138272 and rs12504628), fatigue (rs1042714, rs1138272), anxiety (rs1051303, rs1800450 and rs1131620), impact of the disease (rs10461985 and rs11172113) and HRQOL (rs11172113, rs1042713, rs1138272 and rs12504628). Significant associations were also found between genetic variants and lung function (rs1042713, rs1042717, rs5030737), respiratory muscle strength (rs1130866), peripheral muscle strength (rs1042713, rs1042717, rs11172113, rs11556218) and functional capacity (rs12899618, rs11046966 and rs1138272). This was an exploratory study and more investigations are necessary to confirm the results obtained and to explore deeply the associations and interpretations between genetics and COPD trajectory.
A Doença Pulmonar Obstrutiva Crónica (DPOC) é uma doença multifatorial e heterogénea que apresenta impactos diferentes em pacientes com estadios da doença semelhantes. Isto sugere que outros fatores para além da função pulmonar podem afetar a forma como o paciente experiencia a sua doença. As medidas reportadas pelo paciente (PROs) são um conjunto de variáveis que permitem avaliar a autoperceção e experiência dos doentes em relação à sua doença. Estudos recentes reportaram a existência de associações entre polimorfismos de nucleótidos simples (SNPs) e PROs, mas pouco ainda se sabe sobre estas associações e seu significado. Assim, este estudo teve como objetivo principal explorar possíveis associações entre variantes genéticas específicas e medidas clínicas, entre as quais PROs. Pretendeu também contribuir para a caracterização dos genótipos dos doentes com DPOC em Portugal. Realizou-se um estudo transversal com 60 doentes com DPOC. As PROs avaliadas foram 1) frequência de exacerbações autoreportadas pelos doentes, 2) dispneia com a modified medical Research Council Scale e Borg, 3) fadiga com a Borg, 4) ansiedade e depressão através da escala de ansiedade e depressão hospitalar, 5) impacto da doença com o teste de avaliação da DPOC e 6) qualidade de vida relacionada com a saúde (QVRS) com questionário do hospital de St. George na doença respiratória. Adicionalmente, outras medidas clínicas também foram avaliadas, i. é., função pulmonar, força muscular periférica com dinamometria digital, força dos músculos respiratórios com a medição das pressões respiratórias e capacidade funcional através do teste de levantar e sentar cinco vezes e 1 minuto. Zaragatoas orofaríngeas e amostras de saliva foram recolhidas de todos os pacientes para genotipagem. Foram encontradas associações significativas entre variantes genéticas e dispneia (rs1143634, rs1042717, rs1138272 e rs12504628), fadiga (rs1042714 e rs1138272), ansiedade (rs1051303, rs1800450 e rs1131620), impacto da doença (rs10461985 e rs1172113) e QVRS (rs11172113, rs1042713, rs1138272 e rs12504628). Também foram encontradas variantes significativamente associadas à função pulmonar (rs1042713, rs1042717 e rs5030737), força dos músculos respiratórios (rs1130866), força muscular periférica (rs1042713, rs1042717, rs11172113 e rs11556218) e capacidade funcional (rs12899618, rs11046966 e rs1138272). Este foi um estudo exploratório e mais investigações são necessárias para confirmar os resultados obtidos e para explorar mais profundamente a associação e interpretação entre a genética e a trajetória da DPOC.

This investigation identifies how CAD models of typical automotive body assemblies could be defined to allow a continuous optimisation of the number of iterations required for the final design and the number of variants on the basis of Parametric Associative Design (PAD) and how methodologies for the development of surfaces, parts and assemblies of the automotive body can be represented and structured for a multiple re-use in a collaborative environment of concept phase of a Product Evolution (Formation) Process (PEP). The standardisation of optimised processes and methodologies and the enhanced interaction between all parties involved in product development could lead to improve product quality and reduce development time and hence expenses. The fundamental principles of PAD, the particular methodologies used in automotive body design and the principles of methodical development and design in general are investigated. The role which automotive body engineers play throughout the activities of the PEP is also investigated. The distribution of design work in concept teams of automotive body development and important methodologies for the design of prismatic profile areas is critically analysed. To address the role and distribution of work, 25 group work projects were carried out in cooperation with the automotive industry. Large assemblies of the automotive bodies were developed. The requirements for distributed design work have been identified and improved. The results of the investigation point towards a file based, well structured administration of a concept design, with a zone based approach. The investigation was extended to the process chain of sections, which are used for development of surfaces, parts and assemblies. Important methods were developed, optimised and validated with regard to an update safe re-use of 3D zone based CAD models instead of 2D sections. The thesis presents a thorough description of the research undertaken, details the experimental results and provides a comprehensive analysis of them. Finally it proposes a unique methodology to a zone based approach with a clearly defined process chain of sections for an update-safe re-use of design models.

Diese Arbeit bietet eine solide theoretische Grundlage zu Philanthropie und religiös motivierten Spendenaktivitäten und deren Einfluss auf Wohltätigkeitstrends, Entwicklungszusammenarbeit und einer auf dem Gedanken der sozialen Gerechtigkeit beruhenden Philanthropie. Untersucht werden dafür die Strukturen religiös motivierte Spenden, für die in der islamischen Tradition die Begriffe „zakat“, „Waqf“ oder im Plural auch „awqaf-“ oder „Sadaqa“ verwendet werden, der christliche Begriff dafür lautet „tithes“ oder „ushour“. Aufbauend auf diesem theoretischen Rahmenwerk analysiert die qualitative und quantitative Feldstudie auf nationaler Ebene, wie die ägyptische Öffentlichkeit Philanthropie, soziale Gerechtigkeit, Menschenrechte, Spenden, Freiwilligenarbeit und andere Konzepte des zivilgesellschaftlichen Engagements wahrnimmt. Um eine umfassende und repräsentative Datengrundlage zu erhalten, wurden 2000 Haushalte, 200 zivilgesellschaftliche Organisationen erfasst, sowie Spender, Empfänger, religiöse Wohltäter und andere Akteure interviewt. Die so gewonnen Erkenntnisse lassen aussagekräftige Aufschlüsse über philanthropische Trends zu. Erstmals wird so auch eine finanzielle Einschätzung und Bewertung der Aktivitäten im lokalen Wohltätigkeitsbereich möglich, die sich auf mehr als eine Billion US-Dollar beziffern lassen. Die Erhebung weist nach, dass gemessen an den Pro-Kopf-Aufwendungen die privaten Spendenaktivitäten weitaus wichtiger sind als auswärtige wirtschaftliche Hilfe für Ägypten. Das wiederum lässt Rückschlüsse zu, welche Bedeutung lokale Wohltätigkeit erlangen kann, wenn sie richtig gesteuert wird und nicht wie bislang oft im Teufelskreis von ad-hoc-Spenden oder Hilfen von Privatperson an Privatperson gefangen ist. Die Studie stellt außerdem eine Verbindung her zwischen lokalen Wohltätigkeits-Mechanismen, die meist auf religiösen und kulturellen Werten beruhen, und modernen Strukturen, wie etwa Gemeinde-Stiftungen oder Gemeinde-„waqf“, innerhalb derer die Spenden eine nachhaltige Veränderung bewirken können. Daher bietet diese Arbeit also eine umfassende wissenschaftliche Grundlage, die nicht nur ein besseres Verständnis, sondern auch den nachhaltiger Aus- und Aufbau lokaler Wohltätigkeitsstrukturen in Ägypten ermöglicht. Zentral ist dabei vor allem die Rolle lokaler, individueller Spenden, die beispielsweise für Stiftungen auf der Gemeindeebene eingesetzt, wesentlich zu einer nachhaltigen Entwicklung beitragen könnten – und das nicht nur in Ägypten, sondern in der gesamten arabischen Region. Als konkretes Ergebnis dieser Arbeit, wurde ein innovatives Modell entwickelt, dass neben den wissenschaftlichen Daten das Konzept der „waqf“ berücksichtigt. Der Wissenschaftlerin und einem engagierten Vorstand ist es auf dieser Grundlage gelungen, die Waqfeyat al Maadi Community Foundation (WMCF) zu gründen, die nicht nur ein Modell für eine Bürgerstiftung ist, sondern auch das tradierte Konzept der „waqf“ als praktikable und verbürgte Wohlstätigkeitsstruktur sinnvoll weiterentwickelt.
This work provides a solid theoretical base on philanthropy, religious giving (Islamic zakat, ‘ushour, Waqf -plural: awqaf-, Sadaqa and Christian tithes or ‘ushour), and their implications on giving trends, development work, social justice philanthropy. The field study (quantitative and qualitative) that supports the theoretical framework reflects at a national level the Egyptian public’s perceptions on philanthropy, social justice, human rights, giving and volunteering and other concepts that determine the peoples’ civic engagement. The statistics cover 2000 households, 200 Civil Society Organizations distributed all over Egypt and interviews donors, recipients, religious people and other stakeholders. The numbers reflect philanthropic trends and for the first time provide a monetary estimate of local philanthropy of over USD 1 Billion annually. The survey proves that the per capita share of philanthropy outweighs the per capita share of foreign economic assistance to Egypt, which implies the significance of local giving if properly channeled, and not as it is actually consumed in the vicious circle of ad-hoc, person to person charity. In addition, the study relates local giving mechanisms derived from religion and culture to modern actual structures, like community foundations or community waqf that could bring about sustainable change in the communities. In sum, the work provides a comprehensive scientific base to help understand- and build on local philanthropy in Egypt. It explores the role that local individual giving could play in achieving sustainable development and building a new wave of community foundations not only in Egypt but in the Arab region at large. As a tangible result of this thesis, an innovative model that revives the concept of waqf and builds on the study’s results was created by the researcher and a dedicated board of trustees who succeeded in establishing Waqfeyat al Maadi Community Foundation (WMCF) that not only introduces the community foundation model to Egypt, but revives and modernizes the waqf as a practical authentic philanthropic structure.

Background: Infertility has become a growing concern across the world as cases continue to increase each year. Research has now shifted to identifying novel biomarkers to predict male fertility. While mtDNAcn has recently been found to show promising results as potential biomarker, its regulation remains unclear. Method: Triplex probe-based PCR was used to quantify mtDNA levels, while 850K Array was used to measure methylation levels. A-clustering algorithm followed by generalized estimating equations (GEE) lead to clustering of individual CpG sites, containing a minimum of 2 CpGs within 1000 base pairs of each other. These clusters were used for analysis of the association between mtDNAcn and DNA methylation within sperm. Metascape1 was used to annotate gene ontology terms. Result: Generalized estimating equation model analysis produced 6,038 FDR significant (q Conclusion: Thus, we show that sperm mtDNAcn is strongly associated with sperm DNA methylation and the associated implicates mtDNAcn as an influence on infertility.

碩士
逢甲大學
統計學系統計與精算碩士班
106
Copy number variation (CNV) is a kind of genetic variation with abnormal fragment copies. Comparative the sequencings between case and control groups could detect the disease associated with CNVs. In this research, we focus on a specific issue about combining test statistics in the CNV association study. The absolute copy number for each window between case and control groups are compared, and then the test statistics are combined to identify the significant disease associated CNVs. The corresponded statistical methods are evaluated via simulation studies.

博士
中山醫學大學
醫學研究所
104
Aims: This dissertation consists of two parts: (1) To compare alterations of mitochondria DNA (mtDNA) copy number, single nucleotide polymorphisms (SNPs), and oxidative damage of mtDNA in clinically stable patients with bipolar I disorder (BD) and normal controls. (2) The same research topics were investigated between patients of major depressive disorder (MDD) and normal controls. Methods: Patients met DSM-IV diagnostic criteria for BD and MDD were recruited from the psychiatric outpatient clinic at a medical center in Central Taiwan. They were clinically stable and their medications had not changed for at least the preceding two months. Exclusion criteria were substance-induced psychotic disorder, eating disorder, anxiety disorder or illicit substance abuse. All participants had no history of chronic medical illness, no indication of acute infection and were not pregnant. Comparison subjects did not have any history of major psychiatric disorders and they were non-smokers. By analyzing peripheral blood leukocytes, copy number, SNPs and oxidative damage of mtDNA were compared between patients and controls. Results: Forty BD patients, 40 MDD patients and 70 comparison subjects were included in this study. The median age of the subjects was 42, 41.5 and 38 years in MDD, BD and comparison groups, respectively. Leukocyte mtDNA copy number was significantly lower in BD and MDD patients than that of the comparison group (p<0.001 and p=0.037). All patients had significantly higher mitochondrial oxidative damage than the comparison group. The SNP of mtDNA C5178A and A10398G were similar in patients and control groups. After generalized linear model adjusting with related variables, mtDNA copy number was still significantly lower both in BD (p<0.001) and MDD group (p<0.001). MtDNA oxidative damage was positively correlated with age. Antipsychotic use was negatively associated with mtDNA copy number (p=0.036) in MDD group. Conclusions and Suggestions: Possible involvement of oxidative damage and mitochondria in the pathophysiology of BD and MDD needs more large-scale studies. Future study of mitochondrial dysfunction in affective disorders may bring some light in the development of disease biomarker. The study is cross-sectional with no longitudinal follow up. This relationship between mitochondrial dysfunction and affective disorders was correlational instead of causal. The study cohort is clinically stable and generalizability of our result to other cohort should be cautiously considered.

博士
國防醫學院
生命科學研究所
102
Hypertension is an important public health problem in Taiwan and in the world. Although many large-scale genome-wide association studies (GWAS) have been performed, few study identified replicable and large-impact hypertension loci, not to mention the scanty Chinese studies. Young onset hypertension (YOH) is considered as a more promising target disorder to investigate than the late-onset one due to its stronger genetic component. To map YOH genetic variants, we carried out GWAS to search for hypertension susceptibility loci/genes with whole genome SNPs, CNVs and gene expression profiles. This investigation was consisted of 3 studies. The first part is a three-stage genome-wide association study using SNPs as genetic markers (SNPs-GWAS), combining 1st-stage multilocus GWAS (400 age- and sex-matched pairs), 2nd-stage gene expression analysis, and 3rd-stage multilocus confirmatory study (992 matched pairs). The second part is a two-stage genome-wide CNVs association study (CNVs-GWAS) consisting of an usual first stage GWAS (200 matched pairs) to find potential susceptibility CNV regions and a second stage confirmatory association study with an independent set of samples (199 matched pairs). Gene expression profiles were used to find differentially expressed genes among those implicated in both the first and second stages of the study. The third part is a two-stage genome-wide gene expression association study (GEs-GWAS), consisting of a regular GWAS in the 1st - stage (126 YOHs and 149 controls) to find the differentially expressed genes and a further confirmation with an independent set of samples (127 YOHs and 150 controls). We also integrated the gene expression data and SNP data to find eSNPs. In the SNPs-GWAS, a total of six SNP septets flanking the C1orf135, GSN, LARS, and ACTN4 remained significant in all three stages. Among them, the septet flanking ACTN4 and LARS was also associated with blood pressure/hypertension in two external replication studies: Hong Kong Hypertension Study (HKHS) and WTCCC hypertension study. In the CNVs-GWAS, 11 CNVs regions involving 14 genes were identified. In the GEs-GWAS, 9 genes were significantly associated with hypertension in both the first- and second-stage. Among these genes, ZRANB1, FAM110A, PREP, ANKRD9 and LAM2 were also differentially expressed in an existing database of hypertensive mouse model (GSE19817). Our study identified several previously unknown YOH loci/genes in Han Chinese. Identification of these genes enriches hypertension susceptibility gene list, thereby shedding light on the etiology of hypertension in Han Chinese.

L’hypertension artérielle essentielle (HTA) est une pathologie complexe, multifactorielle et à forte composante génétique. L’impact de la variabilité dans le nombre de copies sur l’HTA est encore peu connu. Nous envisagions que des variants dans le nombre de copies (CNVs) communs pourraient augmenter ou diminuer le risque pour l’HTA. Nous avons exploré cette hypothèse en réalisant des associations pangénomiques de CNVs avec l’HTA et avec l’HTA et le diabète de type 2 (DT2), chez 21 familles du Saguenay-Lac-St-Jean (SLSJ) caractérisées par un développement précoce de l’HTA et de la dyslipidémie. Pour la réplication, nous disposions, d’une part, de 3349 sujets diabétiques de la cohorte ADVANCE sélectionnés pour des complications vasculaires. D’autre part, de 187 sujets de la cohorte Tchèque Post-MONICA (CTPM), choisis selon la présence/absence d’albuminurie et/ou de syndrome métabolique. Finalement, 134 sujets de la cohorte CARTaGENE ont été analysés pour la validation fonctionnelle. Nous avons détecté deux nouveaux loci, régions de CNVs (CNVRs) à effets quantitatifs sur 17q21.31, associés à l’hypertension et au DT2 chez les sujets SLSJ et associés à l’hypertension chez les diabétiques ADVANCE. Un modèle statistique incluant les deux variants a permis de souligner le rôle essentiel du locus CNVR1 sur l’insulino-résistance, la précocité et la durée du diabète, ainsi que sur le risque cardiovasculaire. CNVR1 régule l’expression du pseudogène LOC644172 dont le dosage est associé à la prévalence de l’HTA, du DT2 et plus particulièrement au risque cardiovasculaire et à l’âge vasculaire (P<2×10-16). Nos résultats suggèrent que les porteurs de la duplication au locus CNVR1 développent précocement une anomalie de la fonction bêta pancréatique et de l’insulino-résistance, dues à un dosage élevé de LOC644172 qui perturberait, en retour, la régulation du gène paralogue fonctionnel, MAPK8IP1. Nous avons également avons identifié six CNVRs hautement hérités et associés à l'HTA chez les sujets SLSJ. Le score des effets combinés de ces CNVRs est apparu positivement et étroitement relié à la prévalence de l’HTA (P=2×10-10) et à l’âge de diagnostic de l’HTA. Dans la population SLSJ, le score des effets combinés présente une statistique C, pour l’HTA, de 0.71 et apparaît aussi performant que le score de risque Framingham pour la prédiction de l’HTA chez les moins de 25 ans. Un seul nouveau locus de CNVR sur 19q13.12, où la délétion est associée à un risque pour l’HTA, a été confirmé chez les Caucasiens CTPM. Ce CNVR englobe le gène FFAR3. Chez la souris, il a été démontré que l’action hypotensive du propionate est en partie médiée par Ffar3, à travers une interférence entre la flore intestinale et les systèmes cardiovasculaire et rénal. Les CNVRs identifiées dans cette étude, affectent des gènes ou sont localisées dans des QTLs reliés majoritairement aux réponses inflammatoires et immunitaires, au système rénal ainsi qu’aux lésions/réparations rénales ou à la spéciation. Cette étude suggère que l’étiologie de l’HTA ou de l’HTA associée au DT2 est affectée par des effets additifs ou interactifs de CNVRs.
Essential hypertension (HT) is a multifactorial complex disease with a strong genetic component. However, little is known about the effects of copy number variance on HT. We hypothesized common Copy Number Variants (CNVs) could increase or decrease the risk for HT. We performed GWAS of CNVs with HT and, with HT and Type 2 Diabetes (T2D), in 21 families of the Saguenay-Lac-St-Jean region of Quebec (FC) affected by early-onset hypertension and dyslipidemia. Replication was tested in a cohort of 3349 unrelated diabetic subjects of Caucasian origin from the ADVANCE trial. Replication was also tested in 187 individuals from the Czech Post-Monica (CPM) cross-sectional survey, ascertained by the presence/absence of albuminuria and/or metabolic syndrome. We performed locus-specific transcriptional analyses in 134 subjects from the CARTaGENE population cohort. We identified two CNV Regions (CNVRs), at 17q21.31, associated with HT and T2D in FC and associated with hypertension in ADVANCE diabetics. A statistical model of association including both CNVRs underlined the main effect size of CNVR1 on insulin resistance, T2D early onset and duration, and risk for cardiovascular diseases (CVD). CNVR1 appeared to influence LOC644172 expression, whose transcript abundance was associated with the prevalence of HT and T2D, and strongly with the risk of CVD and vascular age (P<2×10-16). Our results suggest carriers of copy-number gain at these 17q21.31 loci, principally at the CNVR1 locus, undergo premature β-cell functional deregulation and insulin resistance, due to increase dosage of the LOC644172 pseudogene, which might in turn affect the regulation of expression of its functional paralog, MAPK8IP1. We also report six different CNVR loci, highly heritable and contributing to the risk of hypertension, in French Canadians. The combined CNV risk score appeared robustly related to prevalence of hypertension (p=2×10-10) and age at diagnosis of hypertension. In FC, this combined CNV risk score model showed a C-statistic of 0.71 for HT and appeared as powerful as Framingham HT risk score in predicting hypertension in individuals aged less than 25. We validated the association of a new locus, 19q13.12 deletion-CNVR, with hypertension, in CPM. FFAR3 surrounds this 19q13.12 deletion-CNVR. It has been demonstrated that in mice, a portion of propionate hypotensive effect is mediated by Ffar3, and involves a cross-talk between the gut microbiota and the renal-cardiovascular system. The identified CNVRs appear to influence genes and QTLs mainly related to immune and inflammatory responses and renal damaged and repair. Some CNVRs are exclusive to primates. This study suggests that additive and interactive actions of multiple copy-number variants are involved in the etiology of hypertension or of hypertension associated with T2D.

Le Syndrome d’Impatiences Musculaires de l’Éveil (SIME) est une maladie neurologique caractérisée par un besoin urgent de bouger les jambes. C’est également l’une des causes les plus fréquentes d’insomnie. C’est une maladie très répandue, avec une prévalence de presque 15 % dans la population générale. Les maladies multifactorielles comme le SIME sont souvent le résultat de l’évolution d’une composante génétique et d’une composante environnementale. Dans le cadre du SIME, les études d’association génomique ont permis l’identification de 4 variants à effet modéré ou faible. Cependant, ces quatre variants n’expliquent qu’une faible partie de la composante génétique de la maladie, ce qui confirme que plusieurs nouveaux variants sont encore à identifier. Le rôle des déséquilibres génomiques (Copy Number Variations ou CNVs) dans le mécanisme génétique du SIME est à ce jour inconnu. Cependant, les CNVs se sont récemment positionnés comme une source d’intérêt majeur de variation génétique potentiellement responsable des phénotypes. En collaboration avec une équipe de Munich, nous avons réalisé deux études CNVs à échelle génomique (biopuces à SNP et hybridation génomique comparée (CGH)) sur des patients SIME d’ascendance germanique. À l’aide d’une étude cas-contrôle, nous avons pu identifier des régions avec une occurrence de CNVs différentes pour les patients SIME, comparés à différents groupes contrôles. L’une de ces régions est particulièrement intéressante, car elle est concordante à la fois avec des précédentes études familiales ainsi qu’avec les récentes études d’associations génomiques.
Restless Legs syndrome (RLS) is a neurological disorder characterized by the urge to move one’s limbs. It is also one of the most frequent causes of insomnia. The prevalence of RLS is estimated to be around 15% in the general population. Complexes disorders like RLS are often the result of the evolution of genetic and environmental components. For RLS, recent Genome Wide Association Study (GWAS) have identified four variants with mild to moderate effects. However, those four variants explain only a small part of the disease heritability and thus, we expect that many new variants are still to be found. The impact of Copy-Number Variation (CNV) in the genetic mechanism of RLS is still unknown. However, many studies have recently position the CNVs as a significant source of genetic variation potentially responsible of phenotypes. In collaboration with a team from Munich, we conducted two genome-wide CNVs studies (Genome Wide SNP chips and Comparative Genomic Hybridization (CGH)) on RLS patients from Germany. Using cases-controls studies, we identified regions with a different occurrence of CNVs for RLS patients, compared to different groups of controls. One of these regions is particularly interesting, as it has already been identified by both linkage and association studies.

碩士
國立臺灣大學
臨床醫學研究所
107
Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by complex inflammatory, neuronal and fibrotic changes. Growth factor plays a key regulator of neuronal plasticity, and a crucial role in tissue repair and emphysema pathogenesis. The aims of this study was to determine which blood-based molecules (growth factors) have been evaluated as possible biomarkers to diagnose outcome of chronic obstructive pulmonary disease (COPD), to be correlated with lung function of forced expiratory volume in one second (FEV1% of predicted), and to predict risk of acute exacerbations. Methods: In the present study, patients over 40 and under 100 years of age with COPD (spirometry GOLD stages 1–4) were studied. Lung function, smoking history, medication, eosinophil of peripheral blood and serum concentrations of growth factors were assessed in all participants. There were 11 kinds of growth factors in this study, including NGF(Nerve growth factor-beta), BDNF(Brain-derived neurotrophic factor), EGF(Epidermal growth factor), FGF-2 (fibroblast growth factor-2), HGF( Hepatocyte growth factor), LIF(Leukemia inhibitory factor), PDGF (Platelet-derived growth factor), PLGF Placental growth factor), SCF(Stem cell Factor), VEGF-A and VEGF-D(Vascular endothelial growth factor-D). Spearman rank correlation was used to assess the relationship between growth factors and FEV1 predicted levels. The trend of levels of growth factors across COPD severity (GOLD grading or ABCD group classification) was assessed by the Jonckheere-Terpstra test. We also compared levels of growth factors between subgroups of FEV1% of predicted (< 50% vs. ≥ 50%), eosinophil (≥ 2% vs. < 2%), and frequent acute exacerbation (AE) in the previous year (0-1 vs. 2-3) by the Mann-Whitney U-test. The associations between growth factors and binary outcomes (e.g., GOLD grading 3-4, FEV1% of predicted <50%) were determined using multivariable logistic regression analysis with adjustment with sex, age, smoking status and body mass index. The performance of growth factors to discriminate frequent AE was evaluated by Receiver Operating Characteristic (ROC) curve analysis. The validation using outcome in the next year was also performed. Results: A total of 138 participants were enrolled who male is predominant (98.6%) and with a mean age of 68.3 years (standard deviation [SD], 9 years). The mean FEV1 predicted levels were 55.7% (SD, 18.4%). Number of GOLD stages 1–4 was 16 (11.6%), 67 (48.6%), 45 (32.6%) and 10 (7.2%) respectively. Number of COPD group classification A, B, C and D was 58 (42.0%), 28 (20.3%), 30 (21.7%), and 22 (15.9%) respectively. No significant correlation between the 11 growth factors and FEV1 predicted levels was found. There were no significant trend of levels of the 11 growth factors across GOLD grading or COPD group classification. There were no significant difference in levels of the 11 growth factors between subgroup of FEV1 predicted (< 50% vs. ≥ 50%) and eosinophil (≥ 2% vs. < 2%). Notably, serum levels of both FGF-2 and VEGF-D were significantly decreased in patients with frequency of acute exacerbations of COPD (AECOPD) compared with patients with infrequency of AECOPD (both P < 0.05) in previous year. The ROC curves showed the area under the curve (AUC) of FGF-2 was 0.704 (95% confidence interval [CI], 0.620 to 0.778, P = 0.010), the optimum cut point for Youden index was ≤4.76 with a sensitivity of 81.8% and a specificity of 62.2%. Another AUC of VEGF-D was 0.700 (95% CI, 0.616 to 0.775, P = 0.004), its Youden index is optimally ≤10.02 with a sensitivity of 100% and a specificity of 43.3%. After combining FGF-2 and VEGF-D in the logistic regression, the result showed that the AUC was 0.777 (95% CI, 0.697 to 0.844, P < 0.001). A total of 112 participants were enrolled for validation study in the next year. Higher FGF-2 level was associated with a lower risk of acute exacerbations of COPD one year later (odds ratio, 0.972; 95% CI, 0.949-0.997). The ROC curves showed the area under the curve (AUC) of FGF-2 was 0.614 (95% CI, 0.518 to 0.705, P = 0.032), the optimum cut point for Youden index was ≤9.12. Higher NGF was associated with a lower risk of frequent AE of COPD one year later(odds ratio, 0.93; 95% CI, 0.87-0.99).Similarly, using the ROC curve, the AUC of the NGF was 0.797 (P < 0.001), which reached an acceptable discriminating power for predict of frequency of acute exacerbations of COPD, the optimum cut point for the Younden index is ≤ 25.23. Conclusion: FGF-2 and VEGF-D concentrations are associated with increased frequency of acute exacerbations of COPD in previous year. FGF-2 was used to predict acute exacerbation of COPD after one year later. For predicting acute exacerbation, if combined with other growth factors (eg, FGF-2, VEGF-D, NGF, etc.), the prediction sensitivity should be improved. Therefore, measuring serum VEGF-D, FGF-2 and NGF concentrations in patients with COPD should be a sensitive indicator for predictive acute exacerbation of patients. Therefore, this may be used as a biomarker for COPD.

INTRODUCTION Phthalates, a chemical class of plasticizers, are ubiquitous in the environment and recognized as endocrine disrupting compounds (EDCs). Recent data suggest that oxidative stress is a potential mediator of poor male reproductive health associated with phthalate exposure. Mitochondria are implicated in the production of excess oxidative stress and sperm mitochondrial copy number (MtCopy) and deletions (MtDeletion) have been linked with male infertility. However, little is known about the relationship of these mitochondrial biomarkers in sperm with phthalate exposure and oxidative stress. OBJECTIVES To examine associations of urinary phthalate metabolites and isoprostane concentrations on sperm MtCopy and MtDeletions in male partners undergoing assisted reproductive technologies (ART). METHODS A total of (n=97) sperm samples were collected from male partners undergoing ART at Baystate Medical Center, in Springfield, MA from 2014 to 2016 as part of the Sperm Environmental Epigenetics and Development Study (SEEDS). Seventeen urinary phthalate metabolites (n=103) were analyzed by the Centers for Disease Control using tandem mass spectrometry. 15-F2t-Isoprostane (n=101) was measured using a competitive enzyme-linked immonsorbent assay in urine of male individuals. A triplex Taqman probe-based qPCR method was developed for relative quantification of genomic DNA, MtCopy and MtDeletions. Multivariable linear or logistic regression was employed to examine associations with age, BMI, batch and current smoking status with each outcome to determine confounders used for adjustment. RESULTS Quartiles of MtCopy and MtDeletion were positively associated with the odds of male infertility (p for trend < .0001 and 0.007, respectively). Urinary metabolite concentrations of MCNP displayed a positive association with MtCopy (β=1.56; p =0.03). Urinary MEHP concentrations were positively associated with MtDeletion in only infertile individuals (n=30) (β = 0.075; p = 0.006). Urinary isoprostane concentration was not associated with MtCopy or MtDeletion, but was associated with seven phthalate metabolite concentrations (MEOHP, MEHHP, MBzP, MHBP, MiBP, and MHiBP). CONCLUSIONS To our knowledge, this is the first study to investigate the relationship between sperm MtCopy and MtDeletion with oxidative stress and phthalates. These results suggest that certain phthalate metabolites may be associated with a known biomarker of systemic oxidative stress. Sperm mitochondrial function as measured by MtCopy and MtDeletion may be considered biomarkers of male infertility, although no relationship was shown between mitochondrial outcomes and oxidative stress. Future research is investigating these relationships with developmental outcomes including embryo quality.

L' Asma, la Rinite e la Bronco-pneumopatia cronica ostruttiva (BPCO) sono malattie respiratorie comuni in tutto il mondo, caratterizzate da infiammazione cronica locale e sistemica delle vie aeree e da aumentata reattività bronchiale, che contribuiscono in modo sostanziale alla morbilità e mortalità negli adulti dei paesi occidentali. Sono malattie complesse ed eterogenee derivate dall'interazione di fattori genetici ed ambientali. Diversi geni, ciascuno con un piccolo effetto, sono verosimilmente coinvolti nello sviluppo di queste malattie e possono contribuire alla variabilità del fenotipo in relazione all’ esposizione ambientale. Molti geni sono riportati in letteratura in associazione ad una, due o tutte e tre le malattie, sebbene i risultati di questi studi non sempre sono consistenti. Questo lavoro è parte del progetto GEIRD (Gene Environment Interaction Respiratory Diseases), uno studio di popolazione caso-controllo, che ha lo scopo di chiarire il ruolo dei fattori genetici ed ambientali in sviluppo, persistenza, gravità e controllo delle malattie infiammatorie. In particolare, la tesi di dottorato qui presentata si focalizza su uno studio di associazione di geni candidati in un' ampia e ben caratterizzata popolazione di soggetti italiani, allo scopo di identificare geni di suscettibilità ad asma, rinite e BPCO e geni di suscettibilità che possono essere comuni alle tre patologie. Un totale di 1175 soggetti, comprendenti soggetti affetti da Asma, Rinite e BPCO (casi) e soggetti non affetti da malattie infiammatorie delle vie aeree (controlli) sono stai arruolati nello studio. E' stata creata una banca di DNA di questi soggetti coinvolti. I geni candidati per lo studio sono stati scelti sulla base dei dati di letteratura, considerando studi di singoli geni, GWAS (studi di scansione sull’ intero genoma) e meta-analisi. È stato selezionato un gruppo di 69 geni coinvolti in processi biologici potenzialmente correlati con le patologie oggetto dello studio, quali l'infiammazione, l'immunità innata, l' immuno-regolazione, lo stress ossidativo, il metabolismo degli xenobiotici, la regolazione dell' equilibrio proteasi-antiproteasi e il rimodellamento tissutale. Un pannello di 384 “Tag-SNP”, rappresentative dei geni candidati oggetto dello studio, è stato sviluppato per l’ analisi con il sistema di genotipizzazione multipla GoldenGate (Illumina). È stato effettuato uno studio di associazione a singolo locus e a loci multipli per valutare l'associazione con i seguenti fenotipi: asma corrente, asma passato, asma totale, asma atopico corrente, rinite allergica e non allergica, rinite totale, e presenza di sintomi respiratori cronici. Una associazione statisticamente significativa (p<0,01) è stata osservata fra il gene IL-13(5q31) e l’ asma passato, i geni SPINK-5 (5q31-q32) e GSTP-1 (11q13) e la rinite non atopica, il gene NOS-1 (12q24.2) e la presenza di sintomi respiratori cronici. Un dato interessante che è emerso da questo studio è la presenza di associazione di polimorfismi nel gene IL1RL-2 (2q12) con più fenotipi (asma corrente, asma atopico corrente, presenza di sintomi respiratori cronici, rinite non allergica, e rinite totale) suggerendo un possibile ruolo di questo gene in tutte le patologie respiratorie studiate. È stato approfondito lo studio per questi geni mediante un’ analisi di associazione degli aplotipi. Questo ulteriore studio ha confermato le associazioni trovate nell’ analisi a singolo locus e il coinvolgimento dei geni IL-13, SPINK-5, GSTP-1, NOS-1 e IL1RL-2 nella suscettibilità alle malattie respiratorie infiammatorie. I risultati di questo studio potranno essere utilizzati in futuro per lo sviluppo di nuovi test genetici molecolari per l’identificazione precoce di sottogruppi di pazienti che necessitano di terapie specifiche o che hanno una suscettibilità individuale a specifici fattori di rischio ambientale mediante la determinazione del loro profilo di rischio genetico. Nell’era post-genomica, la ricerca e l’identificazione dei geni associati alle malattie complesse sono ancora una delle principali sfide per la comprensione profonda delle malattie umane complesse. Una migliore conoscenza dei meccanismi patogenetici e l'identificazione di marcatori molecolari di malattia e di profili genomici associati a particolari manifestazioni della malattia e al decorso clinico, offrirà nuovi bersagli per la terapia farmacologica e aprirà la strada a possibili applicazioni future per il trattamento e la prevenzione delle malattie, per mezzo di una definizione più accurata della prognosi e dello sviluppo di terapie più specifiche o addirittura individuali.
Asthma, Rhinitis and Chronic Obstructive Pulmonary Disease (COPD) are common respiratory diseases worldwide, characterized by systemic and local chronic inflammation of the airways and increasing bronchial responsiveness, that contribute substantially to morbidity and mortality in adults living in the developed world. They are complex and heterogeneous diseases resulting from interaction between genetic and environmental factors. Several genes, each with a small effect, are likely involved in the development of these diseases and might contribute to the phenotype variability according to environmental exposure. Many candidate genes are reported in the literature data in association to one, two or all three diseases, even if results of these studies are not always consistent. This work is a part of the GEIRD (Gene Environment Interaction Respiratory Diseases) project, a population-based case-control study, aimed to elucidate the role of environment and genetic factors in the occurrence, persistence, severity and control of inflammatory airway diseases. In particular, the PhD thesis project here presented is focused on candidate gene association analysis in a large and accurately defined series of Italian subjects, in order to identify genes involved in the susceptibility to Asthma, Rhinitis and COPD and susceptibility genes that may be common to all the three diseases. A total of 1175 individuals, including subjects affected by asthma, rhinitis and COPD (cases) and unaffected by airways inflammatory diseases (controls), have been enrolled. A DNA bank, from all the subjects participating to the study, was created. Candidate genes for the study was chosen on the basis of the analysis of literature data, considering single genes studies, GWAS and meta-analyses. A group of 69 genes, involved in pathways related to the all three studied diseases, as inflammation, innate immunity and immunoregulation, oxidative stress and metabolism of xenobiotics, regulation of the protease-antiprotease equilibrium, and tissue remodelling, were selected. A panel of 384 Tag SNPs, representative of the candidate genes, was genotyped by a customized multiplexed GoldenGate Genotyping assay (Illumina). A single-locus and multi-locus association analysis was conducted to evaluate association with the following phenotypes: current asthma, past asthma, total asthma (current and past), current atopic asthma, allergic rhinitis, non allergic rhinitis, total rhinitis (allergic and non allergic), and subjects presenting with chronic respiratory symptoms. A significant association (p<0,01) was observed between IL-13 (5q31) and past asthma, both SPINK-5 (5q31-q32) and GSTP-1 (11q13) and non-atopic rhinitis, NOS-1 (12q24.2-24.31) and chronic respiratory symptoms. More interestingly, polymorphisms in IL1RL-2 gene (2q12) were found associated to multiple phenotypes (current asthma, current atopic asthma, chronic respiratory symptoms, non atopic rhinitis, and total rhinitis) suggesting a possible role for this gene in all the studied respiratory diseases. Therefore, we decide to deepen the study performing an haplotype association analysis for these genes. This additional study confirmed the single-locus associations found and the involvement of IL-13, SPINK-5, GSTP-1, NOS-1 and IL1RL-2 genes in the susceptibility to inflammatory respiratory diseases. The results of this study can be used in the future for the development of new molecular genetic tests for the early identification of subgroups of patients who need a specific therapy or having an individual susceptibility to specific environmental risk factors, by the determination of their genetic risk profile. In the post-genomic era, searching and identification of genes associated with complex diseases are still one of the main challenges for dissecting human complex diseases. A better understanding of pathogenic mechanisms and the identification of molecular markers of disease and genomic profiles, associated to particular diseases phenotypes and clinical outcomes, will be offering new targets for pharmacological therapy and will be opening the way to possible future applications in disease treatment and prevention, by a more accurate prognosis determination and a more specific or even individual therapies.

碩士
國立中山大學
生物科學系研究所
106
Background: Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the world, is a chronic inflammatory disease of the airway characterized by “persistent airflow limitation that is usually progressive”. COPD is recognized as a complex and heterogeneous syndrome. Significant heterogeneity exists within COPD with respect to clinical presentation, physiology, imaging, response to therapy, decline in lung function, and survival. Currently, there are neither consensus phenotypes classification nor useful biomarkers in COPD. Serum IgE and blood eosinophil, which are easy to measure, have been used as biomarkers in asthma. This study aimed to evaluate the clinical utility of serum IgE levels and blood eosinophil counts in COPD patients. Methods: We conducted a prospective observational study in Kaohsiung Medical University Hospital. From Jan 1, 2016 to Dec 31, 2017, we enrolled 208 patients with COPD into this study. These patients were followed till Mar 31, 2018, with a mean follow-up period of 18.8 months. Of the 208 enrolled patients, 190 with complete data were analyzed. We compared clinical features and exacerbation frequency between COPD patients with serum IgE < 100 KU/L vs. ≥ 100 KU/L, blood eosinophil counts < 300/µL vs. ≥ 300/µL and blood eosinophil < 4% vs. ≥ 4% Results: Of the 190 COPD patients analyzed in this study, 56 (29.5%) patients had moderate or severe acute exacerbation events, 55 (28.9%) had blood eosinophil ≥ 300/µL, 65 (34.2%) had blood eosinophil ≥ 4%, and 83 (45.1%) had serum IgE ≥ 100 KU/L. COPD patients with blood eosinophil ≥ 300/µL or > 4% had significantly higher risk of acute exacerbation (OR = 2.80, 95% CI = 1.44-5.44, P = 0.011; OR = 2.35, 95% CI = 1.23-4.48, P = 0.093). Serum IgE ≥ 100 KU/L were not associated with higher risk of acute exacerbation (OR = 0.81, 95% CI = 0.43-1.55, P = 0.533). In multivariate analysis, positive bronchodilator response, diffusion capacity of the lung for carbon monoxide (DLCO) and blood eosinophil percentage were significantly associated with acute exacerbation risk. For every 1% increment in blood eosinophil, the risk of exacerbation increased by 25% (OR = 1.25, 95% CI = 1.09-1.43, P = 0.001). Conclusion: Blood eosinophil count and percentage were significantly associated with acute exacerbation in COPD. For every 1% increment in blood eosinophil, the risk of exacerbation increased by 25%. Serum IgE levels were not associated with risk of COPD acute exacerbation. Blood eosinophil are easily available and can serve as useful biomarkers in COPD. We suggest measuring blood eosinophil counts or percentage routinely in COPD to evaluate the risk of future acute exacerbation.

Les recherches menées pour comprendre les troubles du spectre autistique (TSA) et la schizophrénie (SZ) ont communément utilisé une approche dite descendante, partant du diagnostic clinique pour investiguer des phénotypes intermédiaires cérébraux ainsi que des variations génétiques associées. Des études transdiagnostiques récentes ont remis en question ces frontières nosologiques, et suggèrent des mécanismes étiologiques imbriqués. L’approche montante propose de composer des groupes de porteurs d’un même variant génétique afin d’investiguer leur contribution aux conditions neuropsychiatriques (NPs) associées. Les variations du nombre de copies (CNV, perte ou gain d’un fragment d’ADN) figurent parmi les facteurs biologiques les plus associés aux NPs, et sont dès lors des candidats particulièrement appropriés. Les CNVs induisant un risque pour des conditions similaires, nous posons l’hypothèse que des classes entières de CNVs convergent sur des dimensions d’altérations cérébrales qui contribuent aux NPs. L’imagerie fonctionnelle au repos (rs-fMRI) s’est révélée un outil prometteur en psychiatrie, mais presqu’aucune étude n’a été menée pour comprendre l’impact des CNVs sur la connectivité fonctionnelle cérébrale (FC). Nos objectifs étaient de: 1) Caractériser l’effet des CNVs sur la FC; 2) Rechercher la présence des motifs conférés par ces signatures biologiques dans des conditions idiopathiques; 3) Tester si la suppression de gènes intolérants à l’haploinsuffisance réorganise la FC de manière indépendante à leur localisation dans le génome. Nous avons agrégé des données de rs-fMRI chez: 502 porteurs de 8 CNVs associées aux NPs (CNVs-NP), de 4 CNVs sans association établie, ainsi que de porteurs de CNVs-NPs éparses; 756 sujets ayant un diagnostic de TSA, de SZ, ou de trouble déficitaire de l’attention/hyperactivité (TDAH), et 5377 contrôles. Les analyses du connectome entier ont montré un effet de dosage génique positif pour les CNVs 22q11.2 et 1q21.1, et négatif pour le 16p11.2. La taille de l’effet des CNVs sur la FC était corrélée au niveau de risque psychiatrique conféré par le CNV. En accord avec leurs effets sur la cognition, l’effet des délétions sur la FC était plus élevé que celui des duplications. Nous avons identifié des similarités entre les motifs cérébraux conférés par les CNVs-NP, et l’architecture fonctionnelle des individus avec NPs. Le niveau de similarité était associé à la sévérité du CNV, et était plus fort avec la SZ et les TSA qu’avec les TDAH. La comparaison des motifs conférés par les délétions les plus sévères (16p11.2, 22q11.2) à l’échelle fonctionnelle, et d’expression génique, nous a confirmé l’existence présumée de relation entre les mutations elles-mêmes. À l’aide d’une mesure d’intolérance aux mutations (pLI), nous avons pu inclure tous les porteurs de CNVs disponibles, et ainsi identifier un profil d’haploinsuffisance impliquant le thalamus, le cortex antérieur cingulaire, et le réseau somato-moteur, associé à une diminution de mesure d’intelligence générale. Enfin, une analyse d’exploration factorielle nous a permis de confirmer la contribution de ces régions cérébrales à 3 composantes latentes partagées entre les CNVs et les NPs. Nos résultats ouvrent de nouvelles perspectives dans la compréhension des mécanismes polygéniques à l’oeuvre dans les maladies mentales, ainsi que des effets pléiotropiques des CNVs.
Research on Autism Spectrum Disorder (ASD) and schizophrenia (SZ) has mainly adopted a ‘top-down’ approach, starting from psychiatric diagnosis, and moving to intermediate brain phenotypes and underlying genetic factors. Recent cross-disorder studies have raised questions about diagnostic boundaries and pleiotropic mechanisms. By contrast, the recruitment of groups based on the presence of a genetic risk factor allows for the investigation of molecular pathways related to a particular risk for neuropsychiatric conditions (NPs). Copy number variants (CNVs, loss or gain of a DNA segment), which confer high risk for NPs are natural candidates to conduct such bottom-up approaches. Because CNVs have a similar range of adverse effects on NPs, we hypothesized that entire classes of CNVs may converge upon shared connectivity dimensions contributing to mental illness. Resting-state functional MRI (rs-fMRI) studies have provided critical insight into the architecture of brain networks involved in NPs, but so far only a few studies have investigated networks modulated by CNVs. We aimed at 1) Delineating the effects of neuropsychiatric variants on functional connectivity (FC), 2) Investigating whether the alterations associated with CNVs are also found among idiopathic psychiatric populations, 3) Testing whether deletions reorganize FC along general dimensions, irrespective of their localization in the genome. We gathered rsfMRI data on 502 carriers of eight NP-CNVs (high-risk), four CNVs without prior association to NPs as well as carriers of eight scarcer NP-CNVs. We also analyzed 756 subjects with idiopathic ASD, SZ, and attention deficit hyperactivity disorder (ADHD), and 5,377 controls. Connectome-wide analyses showed a positive gene dosage effect for the 22q11.2 and 1q21.1 CNVs, and a negative association for the 16p11.2 CNV. The effect size of CNVs on relative FC (mean-connectivity adjusted) was correlated with the known level of NP-risk conferred by CNVs. Consistent with results on cognition, we also reported that deletions had a larger effect size on FC than duplications. We identified similarities between high-risk CNV profiles and the connectivity architecture of individuals with NPs. The level of similarity was associated with mutation severity and was strongest in SZ, followed by ASD, and ADHD. The similarity was driven by the thalamus, and the posterior cingulate cortex, previously identified as hubs in transdiagnostic psychiatric studies. These results raised questions about shared mechanisms across CNVs. By comparing deletions at the 16p11.2 and 22q11.2 loci, we identified similarities at the connectivity, and at the gene expression level. We extended this work by pooling all deletions available for analysis. We asked if connectivity alterations were associated with the severity of deletions scored using pLI, a measure of intolerance to haploinsufficiency. The haploinsufficiency profile involved the thalamus, anterior cingulate cortex, and somatomotor network and was correlated with lower general intelligence and higher autism severity scores in 3 unselected and disease cohorts. An exploratory factor analysis confirmed the contribution of these regions to three latent components shared across CNVs and NPs. Our results open new avenues for understanding polygenicity in psychiatric conditions, and the pleiotropic effect of CNVs on cognition and on risk for neuropsychiatric disorders.

碩士
中山醫學大學
營養學研究所
97
Oxidative stress is thought to play a key role in the pathogenesis of COPD. Increasing evidence suggested that individuals with a high intake of antioxidative nutrients, such as vitamins C, E, A, and carotenoids tend to maintain better lung function. However, little has been known about the intakes status of these nutrients in COPD patients in Taiwan. Therefore, this case-controlled study elucidated the differences in plasma and intake levels of vitamin A and various carotenoids as well as the association of the plasma concentration of these nutrients and endogenous and H2O2-induced white blood cells (WBC) DNA damage. In addition, we investigated whether the dietary habits of avoiding “cooling” vegetables and fruits affect the intake of these nutrients. Thirty-two COPD patients, who satisfied the criteria with forced expiratory volume in 1 second (FEV1) % predicted less than 80% and a ratio of FEV1 to forced vital capacity (FVC) less than 0.7, were recruited in this study; whereas, forty-three healthy people, who were ≧ 50 years old and with normal lung function, were recruited as control group. We compared the dietary habits and nutrient intakes using a food frequency questionnaire and a 24-h food recall. Blood samples were collected to measure the level of vitamin A, α-carotene, β-carotene, lutein and lycopene. The results showed that the mean intakes of vitamin A, individual carotenoid except for α-carotene or total carotenoids in COPD patients were significantly lower than those of healthy people. On the other hand, the mean plasma concentrations of vitamin A, individual carotenoid except for lutein and lycopene, or total carotenoids were also significantly lower in COPD patients than those of healthy individuals. Furthermore, we investigated the associations between these nutrients with DNA damage in white blood cells (WBC), because the previous study in our lab showed that the endogenous and H2O2-induced WBC DNA damage of COPD patients were significantly higher than those of healthy people. Pooling the data of the two groups showed that total carotenoids concentration was significantly inversely correlated with the H2O2-induced WBC DNA damage (β= -5.343, p=0.043).However, after adjusted for confounders, the inverse association was not statistically significant. In addition, the sum vegetable and fruit intakes frequency of COPD patients was significantly lower than that of healthy people, especially in cooling items. In both COPD and healthy groups, the total consumption of vegetables and fruits was significantly positively associated with the intake of dietary vitamin A,β-carotene, lutein, and total carotenoids; whereas the consumption of cooling items were positively associated, with a borderline significance, with the intake of vitamin A in both groups after adjustment for confounders. After adjusting for confounders, the total consumption vegetables and fruits, rather than each individual nutrient, reduced the OR for COPD. In summary, COPD patients in Taiwan have lower levels of plasma and of intake of vitamin A and several carotenoids than healthy people. The consumption of cooling foods was positively associated with the total consumption of vegetables and fruits which affect the intake of several antioxidative nutrients.