1,721,139 research outputs found
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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Computational Methods and Epidemiologic Approaches for Revealing the Etiology of Autoimmune Diseases
Full text linkAutoimmune diseases, in which normal tissues are inappropriately attacked by the immune system, are complex diseases driven by a combination of genetic and environmental factors. Most are chronic inflammatory diseases with some treatments available but no known cures, and the disease mechanisms are not completely understood. Epigenetic factors, such as DNA methylation and microRNAs, are affected by genetic and environmental exposures and in turn affect gene expression and thus may play a role in autoimmune disease pathogenesis. In this dissertation, I employ a combination of computational, bioinformatic, statistical, and epidemiologic methods to study the role of epigenetics in autoimmune diseases in humans, and to characterize inflammatory changes in human cell lines.Chapter one introduces some complexities of studying autoimmune diseases in humans and introduces concepts of epigenetics. Chapter two shows that naïve T cells from rheumatoid arthritis patients share DNA methylation sites with fibroblast-like synoviocytes, cells that line joints and are involved in joint inflammation. Chapter three shows that there are differences in DNA methylation in CD4+ and CD8+ T cells from multiple sclerosis patients compared to cells from healthy controls. Chapter four uses genome-wide association study results to implicate specific microRNAs and tissues in pediatric-onset multiple sclerosis. Chapter five shows that the inflammatory cytokine tumor necrosis factor alpha drives DNA methylation and transcriptional changes and activates autoimmune disease genes in endothelial cells. Chapter six is a summary of conclusions and key findings
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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Investigation of Candidate Genes and HLA-Related Risk Factors in a Genetic Study of Autoimmune Disease
Full text linkCollectively autoimmune diseases constitute a major burden to society. Though the etiology of autoimmune diseases remain largely unknown, evidence supports a substantial genetic component. For many autoimmune diseases, twin studies demonstrate a dramatically higher disease concordance rate in monozygotic twins than in dizygotic twins. Genes in the major histocompatibility complex (MHC) region on the short arm of chromosome 6, particularly the human leukocyte antigen (HLA) class II genes, are strongly associated with risk of developing rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and type 1 diabetes (T1D).The MHC class II transactivator gene (CIITA, also called MHC2TA), located on the short arm of chromosome 16, encodes an important transcription factor (CIITA) regulating the genes required for HLA class II MHC-restricted antigen presentation. Thus CIITA is a strong biological candidate for studies of autoimmune disease. Directly adjacent to CIITA lies the C-type lectin domain family 16, member A gene (CLEC16A, previously called KIAA0350). CLEC16A is a sugar binding receptor containing a putative immunoreceptor and was recently identified as a novel T1D and MS susceptibility locus through genomewide association (GWA) studies.HLA may also influence susceptibility to autoimmune disease through other inherited and noninherited mechanisms, in addition to genetic transmission of risk alleles. Evidence for increased maternal-offspring HLA compatibility and differences in both maternal vs. paternal transmission rates (parent-of-origin effects) and nontransmission rates (noninherited maternal antigen (NIMA) effects) in autoimmune diseases have been reported.The investigation described in this dissertation tested hypotheses that (1) the CIITA -168A/G promoter polymorphism (rs3087456) influences susceptibility to RA (Chapter 2); (2) common genetic variation in CIITA influences susceptibility to RA in a case-control study (Chapter 3); (3) common genetic variation in CIITA influences susceptibility to SLE or specific secondary SLE phenotypes (Chapter 4); (4) common genetic variation in CIITA influences susceptibility to MS (Chapter 5); (5) common genetic variation in CLEC16A influences susceptibility to RA (Chapter 6); (6) the HLA class II DRB1 locus influences susceptibility to SLE through maternal-offspring HLA compatibility, parent-of-origin and NIMA effects (Chapter 7); and (7) the HLA classical loci influence susceptibility to T1D through maternal-offspring HLA compatibility, parent-of-origin and NIMA effects (Chapter 8).This dissertation includes the first study to fully characterize common genetic variation in CIITA and CLEC16A, including assesment of haplotypes, sex-specific effects, secondary clinical phenotypes and HLA risk alleles. Results do not provide evidence for association between CIITA and RA or SLE or for association between CLEC16A and RA. Interestingly, this study revealed evidence for an association between the CIITA missense mutation rs4774 and increased risk for MS in the presence of the HLA-DRB1*1501 risk allele. There was no linkage disequilibrium between CIITA and CLEC16A, and the observed association between CIITA and MS in the presence of HLA-DRB1*1501 was independent of the association between CLEC16A and MS.The first studies to examine maternal-offspring HLA compatibility in T1D and HLA-DRB1 parent-of-origin and NIMA effects in SLE, and the largest study to examine maternal-offspring HLA compatibility in SLE and HLA parent-of-origin and NIMA effects in T1D were also performed. No evidence that the HLA-DRB1 locus influences risk for SLE or that the classical HLA loci influence risk for T1D through these novel biological phenomena was revealed
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The role of genetic and environmental immune dysregulation in the etiology of childhood acute lymphoblastic leukemia and other complex diseases
Full text linkThe role of genetic and environmental immune dysregulation in the etiology of childhood acute lymphoblastic leukemia and other complex diseasesAmelia Dale WallaceDoctor of Philosophy in EpidemiologyUniversity of California, BerkeleyProfessor Lisa Barcellos, ChairChildhood acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Epidemiologic studies suggest that of genetic and environmental factors influencing immune dysregulation play an important role in the etiology of the disease. In the following dissertation, we explore three hypotheses, one established and two nascent, wherein potential immunomodulatory risk factors are tested for association with ALL. Allergic disease has long been suspected to play a role in the development of childhood ALL. Studies conducted over the last several decades have yielded mixed results. In the first chapter, we examine the association between allergy, a common immune-mediated disorder, and ALL in the California Childhood Leukemia Study (CCLS), a case-control study of 977 children diagnosed with ALL and 1037 matched controls (1995-2015). History of allergies in the first year of life was obtained from interviews, mainly reported by mothers. Logistic regression analyses were conducted to estimate odds ratios (ORs) and 95% confidence intervals (CIs), controlling for birth order, day care attendance, and mode of delivery. In addition, we conducted meta-analyses with data from the CCLS and 12 published studies and employed a new method to estimate between-study heterogeneity (R_b).Overall, no associations were observed between childhood ALL risk and specific allergy phenotypes or any allergy, as a group. However, having any allergy was associated with an increased risk of ALL among the youngest study participants. In the meta-analysis random-effect models, reduced odds of ALL was associated with hay fever (metaOR=0.65, 95% CI: 0.47, 0.90); however, restricting the analysis to studies that used medical records for assessment of allergy or recently published studies led to null or attenuated results. Overall, our findings do not support a clear association between allergy and childhood ALL. We conclude that the degree to which epidemiological studies can inform the relationship between allergies and risk of childhood ALL is limited by between-study heterogeneity.In the second chapter, we explore a putative germline genetic risk factor that could contribute to the increased incidence of ALL in Hispanics, who have the highest rate of disease (4.3 cases per 100,000 per year). Our current understanding of the complex etiology of childhood ALL has failed to explain this disproportionate burden. Recently, one predominant somatic point mutation signature (TpC>T point mutations) related to the innate immune enzyme APOBEC3B was identified in ALL tumor genomes. A common deletion polymorphism in this gene is prevalent in Hispanics and has been associated with an increased risk of other cancers that have the APOBEC3B-related point mutation signature.We genotyped and tested for association this ~29Kb deletion polymorphism and risk of childhood ALL in 518 cases and 608 controls in the CCLS, where Hispanics account for ~45% of the study population. We found no evidence for germline risk of disease among carriers of the deletion polymorphism, or any SNP in the APOBEC3 gene megalocus in a larger set of 1,083 cases and 1,137 controls. To ensure that ethnic heterogeneity did not mask true associations, local genetic ancestry was inferred with RFMix. Adjustment for local genetic ancestry did not meaningfully alter the observed associations. Further, no specific local genetic ancestry in the APOBEC3 megalocus was independently associated with disease. While somatic mutation induced by the APOBEC3B enzyme may influence tumor progression, there is no evidence that APOBEC3 polymorphisms are associated with disease etiology.Another leading etiologic hypothesis for ALL related to immune dysregulation states that a specific infectious agent – or mis-timing of common infection – early in life causes the disease. In an untargeted viral discovery study previously carried out in the CCLS, we observed high expression of human endogenous retroviruses (HERVs) in diagnostic bone marrow samples. Approximately 8% of the human genome is comprised of HERVs originating from historic retroviral integration into germ cells. The function of HERVs as regulators of gene expression is well established. Less well studied are insertional polymorphisms of HERVs and their contribution to the heritability of complex phenotypes like cancer. The most recent integration of HERV, HERV-K, is expressed in a range of complex human conditions from cancer to neurologic diseases. In an exploratory study to better understand potential links between HERV-K and ALL, we undertook a phenome-wide association study of HERV-K polymorphisms and present the results in the third and final chapter. Using an in-house computational pipeline and whole-genome sequencing data from the diverse 1000 Genomes Phase 3 population (n=2,504), we identified 48 polymorphic HERV-K insertions that are tagged by adjacent SNPs. To test the potential role of polymorphic HERV-K in the heritability of complex diseases, existing databases were queried for enrichment of established relationships between the HERV-K insertion-associated SNPs (hiSNPs), and tissue specific gene expression and disease phenotypes. Overall, hiSNPs for the 48 polymorphic HERV-K sites were statistically enriched (p<1.0E-16) for eQTLs across 44 human tissues. Fifteen of the 48 HERV-K insertions had hiSNPs annotated in the EMBL-EBI GWAS Catalog and cumulatively associated with >100 phenotypes. Experimental factor ontology enrichment analysis suggests that polymorphic HERV-K specifically contribute to neurologic and immunologic disease phenotypes, including traits related to intracranial volume (FDR 2.00E-09), Parkinson’s disease (FDR 1.80E-09), and autoimmune diseases (FDR 1.80E-09). These results provide strong candidates for context-specific study of polymorphic HERV-K insertions in disease-related traits and observed enrichment in immune-related traits aw well as virally induced cancers warrant further study in ALL, despite identifying no existing associations specifically with the disease.Overall, these studies make an important contribution to our understanding of the immune dysregulation that precedes childhood-onset ALL. Specifically, this work has lain to rest existing hypotheses while at the same time generating new ones. Future research building off this work will bring us closer to effective prevention strategies for this devastating disease
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Genomic and Epigenomic Contributions to Autoimmune Disease Heterogeneity
No full textSystemic lupus erythematosus, multiple sclerosis, and Sjögren’s disease are complex and heterogeneous autoimmune diseases of unknown etiology. Disease symptoms and progression differ greatly from person to person with each of these diseases, and the reason for the heterogenous presentation is not fully understood. In this dissertation, I applied epidemiologic, bioinformatic, biostatistical, and computational methods to characterize the role genetic and epigenetic factors play in autoimmune disease heterogeneity. Chapter one covers genetic and epigenetic factors contributing to disease heterogeneity in systemic lupus erythematosus, multiple sclerosis, and Sjögren’s disease. Chapter two describes the results of an investigation into the contributions of genetic ancestry to disease manifestations in systemic lupus erythematosus, finding little contribution of local ancestry to disease symptoms. Chapter three uses epigenetic clocks to assess age acceleration in multiple sclerosis patients related to cognitive performance and diagnosis of Alzheimer’s disease and related dementia and finds accelerated aging in multiple sclerosis patients with worse cognitive outcomes. Chapter four uses machine learning methods to identify Sjögren’s disease patient clusters from DNA methylation data and investigates the underlying differential methylation contributions to these clusters
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Identification of genetic and epigenetic factors in autoimmune disease etiology and treatment response
Full text linkMultiple sclerosis and rheumatoid arthritis are complex autoimmune disease of unknown etiology. Each are result of exposure to a combination of genetic and environmental risk factors. Effective treatments that reduce the rate that normal tissues are attacked by the immune system have been developed; however, the mechanisms underlying disease pathogenesis and treatment response are not completely understood. In this dissertation, I used a combination of epidemiologic, bioinformatic, and computational methods to study the role of gene and environmental interactions, the vitamin D pathway, and DNA methylation in multiple sclerosis and rheumatoid arthritis. Chapter one introduces the genetic, environmental, and epigenetic factors in multiple sclerosis and rheumatoid arthritis. Chapter two describes results from an investigation into gene and environment interaction between genetic risk factors and pregnancy for multiple sclerosis susceptibility finding no evidence for effect modification between genetic susceptibility and pregnancy. Chapter three uses mendelian randomization methods to identify evidence that variation in vitamin D receptor binding is associated with MS susceptibility. Chapter four shows that changes cell-specific DNA methylation are associated with response to treatment with methotrexate among treatment naïve rheumatoid arthritis patients
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Examining the Biological Mechanisms Underlying the Relationship Between Obesity and Multiple Sclerosis Susceptibility
Full text linkBackgroundMultiple sclerosis (MS) is an autoimmune disease of the central nervous system that affects over 400,000 Americans and 2.5 million people worldwide. It is characterized by the presence of inflammation, neurodegeneration, and demyelinating lesions of white and gray matter. Both genetic and environmental factors have been implicated in MS etiology. Several genetic variants, including the human leukocyte antigen HLA-DRB1*15:01 allele within the major histocompatibility complex (MHC) and 110 non-MHC variants, have been identified.Environmental risk factors associated with MS onset include exposure to tobacco smoke,Epstein-Barr virus or infectious mononucleosis, low levels of vitamin D, and most recently,obesity.Obesity is a current public health problem around the world; approximately 35% of adults in the U.S. are obese. Further, obesity has more than doubled in children and quadrupled in adolescents over the past 30 years. Studies over the last decade have demonstrated that early childhood and adolescent obesity are significant risk factors for MS susceptibility. Therefore, the increasing prevalence of obesity could potentially be contributing to higher rates of MS in children and adults.MethodsIn this dissertation, I investigate the association between obesity and MS in several manners in order to understand the causal relationship and underlying biological relationship between these factors. In the first chapter, I examine whether self-reported body size during childhood and adolescence is associated with MS susceptibility, while controlling for several establishedgenetic and environmental risk factors. In the second chapter, I utilize Mendelian randomization to estimate the causal relationship between obesity and MS using a weighted body mass index genetic risk score (BMI GRS) of 97 variants previously identified to be associated with BMI. Additionally, I demonstrate evidence of protein-protein interactions between established gene regions associated with both BMI (n=97) and MS disease susceptibility (n=110), and that a subset of these are significantly associated with MS after adjusting for covariates. In the third chapter, I again examine the causal relationship between obesity and MS onset but instead focus on pediatric-onset MS (disease onset < 18 years). In addition, I examine whether a causal relationship between vitamin D and MS exists in pediatric-onset MS cases and controls, and whether BMI and vitamin D independently contribute to pediatric-onset MS susceptibility. Lastly, in chapter four, I identify genome-wide significant variants associated with serum levels of three adipokines to measure their relationship with MS: plasma soluble leptin receptor, adiponectin, and resistin.SignificanceThis dissertation examines the complex contribution of obesity to MS susceptibility whileaccounting for other genetic and environmental risk factors for the first time. My findingsestablish strong evidence for potential underlying biological mechanisms between increased BMI and MS, identify potential genetic pathways that may be targeted for therapeutics, and indicate that interventions focusing on obesity prevention could in turn reduce the incidence of MS in the population
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Investigating Genetic and Environmental Contributions to Autoimmune Disease Pathogenesis Using Genomic and Computational Approaches
No full textMultiple sclerosis and Sjögren’s disease are complex autoimmune diseases whose underlying causes are not yet fully understood. Both conditions disproportionately affect women and are influenced by a combination of genetic and environmental risk factors, including variants in the major histocompatibility complex and exposures such as Epstein-Barr virus and vitamin D deficiency. While over 230 risk loci have been identified for multiple sclerosis, far fewer have been established for Sjögren’s disease, underscoring gaps in our understanding of its genetic architecture. In this dissertation, I utilize genomic, epidemiologic, computational, and statistical methods to investigate how genetic and environmental risk factors and the vitamin D pathway influence susceptibility to and severity of multiple sclerosis and Sjögren’s disease. Chapter one provides background on the known etiologies of multiple sclerosis and Sjögren’s disease. Chapter two leverages Mendelian randomization methods to show that one vitamin D receptor binding variant previously causally implicated in adult multiple sclerosis was also significantly associated with pediatric onset of multiple sclerosis. Chapter three builds on this work by applying similar Mendelian randomization methods to evaluate the causal role of serum vitamin D in Sjögren’s disease, and to test whether variation in vitamin D receptor binding is associated with Sjögren’s disease susceptibility. Chapter four uses linear regression and linear mixed models to evaluate clinical-demographic and genetic predictors of cognitive performance and physical disability in multiple sclerosis patients, revealing that higher genetic risk was associated with greater improvement in cognitive function scores over time. Chapter five summarizes the main contributions of this dissertation and proposes potential directions for future research. Together, these studies aim to uncover shared and disease-specific biological pathways contributing to autoimmunity and clinical outcomes in multiple sclerosis and Sjögren’s disease
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