Lapatinib is associated with a low incidence of serious liver injury. Previous investigations have identified and confirmed the Class II allele HLA-DRB1*07:01 to be strongly associated with ...lapatinib-induced liver injury; however, the moderate positive predictive value limits its clinical utility. To assess whether additional genetic variants located within the major histocompatibility complex locus or elsewhere in the genome may influence lapatinib-induced liver injury risk, and potentially lead to a genetic association with improved predictive qualities, we have taken two approaches: a genome-wide association study and a whole-genome sequencing study. This evaluation did not reveal additional associations other than the previously identified association for HLA-DRB1*07:01. The present study represents the most comprehensive genetic evaluation of drug-induced liver injury (DILI) or hypersensitivity, and suggests that investigation of possible human leukocyte antigen associations with DILI and other hypersensitivities represents an important first step in understanding the mechanism of these events.
This book completes a landmark six-volume translation of the major writings of Wilhelm Dilthey (1833–1911), a philosopher and historian of culture who continues to have a significant influence on ...philosophy, hermeneutics, and the theory of the human sciences. These volumes make available to English readers texts that represent the full range of Dilthey's work.The works in this volume present Dilthey's most deeply held views about philosophy and how it can guide human practices. System of Ethics (1890) argues that Humean sympathy motivates us only externally and must be replaced with the internally motivated fellow- feeling of solidarity that respects others as ends in themselves. The Essence of Philosophy (1907) demonstrates how philosophy has developed from its traditional metaphysical role to the epistemological and encyclopedic functions that ground and order the natural and human sciences. The work also discloses an orientational function of philosophy that is explored further in "The Types of World-View and Their Development" (1911). Philosophical world- views are important in that they address the existential needs and riddles that grow out of life experience and are not solved by any of the sciences.In addition, the book features three other significant essays. "Present Day Culture and Philosophy" (1898) concerns the challenges to philosophy posed by contemporary culture. "Dream" (1903) is about the thinkers portrayed in Raphael's School of Athens and Dilthey's worries about them breaking up into three divergent groups. Finally, "The Problem of Religion" (1911) considers how religiosity can still inform lived experience in secular times.
Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus ...(EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS (P = 3.5 × 10−36) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio OR = 1.6; 95% confidence intervals 95%CI: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB1*15:01 carriage, absence of HLA-A*02:01, and high anti-EBNA1 antibody levels (OR = 24.9; 95%CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 aa 140 to 149 and EBNA1 aa 431 to 440. HLA gene region was associated with anti-ANO2 antibody levels and HLA-DRB1*04:01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95%CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS.
Potent cytotoxic responses can be mediated by HLA-C both in the context of NK and CD8+ T cells recognition, but with low level cell surface expression and a more restricted peptide binding, this HLA ...distinguishes itself among the class I molecules.3 Interestingly, immunohistology of heart tissue of fetuses deceased from CHB shows CD8+ T cells in the mononuclear cell infiltrates,4 indicating a direct role for HLA class I peptide presentation to CD8+ T cells in the disease pathogenesis. There are many reports of negative DRB1*13 associations in European populations with autoimmune diseases.6 We therefore hypothesise that the protective DRB1*13 association with CHB depends on a general mechanism of protection from inflammation shared among autoimmune diseases, and interpret the observed lack of significantly associated HLA alleles that increase susceptibility to CHB as consistent with the fact that the pathogenic CHB-initiating autoantibodies are generated in the mother. Funding The study was supported by grants from the Swedish Research Council, the Heart-Lung Foundation, the Stockholm County Council, Karolinska Institutet, the Swedish Rheumatism Association, the King Gustaf Vth 80-year Foundation and the Freemason’s in Stockholm Foundation for Children’s Welfare.
Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major ...effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01-HLA-DRB1*15:01 and HLA-DQB1*03:01-HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.
Abstract
Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive ...linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.
The philosopher and historian of culture Wilhelm Dilthey (1833-1911) has had a significant and continuing influence on twentieth-century Continental philosophy and in a broad range of scholarly ...disciplines. This volume is the third to be published in Princeton University Press's projected six-volume series of his most important works. Part One makes available three of his works on hermeneutics and its history:"Schleiermacher's Hermeneutical System in Relation to Earlier Protestant Hermeneutics"(The Prize Essay of 1860); "On Understanding and Hermeneutics" (1867-68), based on student lecture notes, and the "The Rise of Hermeneutics" (1900), which traces the history of hermeneutics back to Hellenistic Greece. All the addenda to this well-known essay are translated here, some for the first time. In them Dilthey articulates three philosophical aporias concerning hermeneutics and projects an ultimate convergence between understanding and explanation.
Part Two provides translations of review essays by Dilthey on Buckle's use of statistical history and on Burckhardt's cultural history; an essay "Friedrich Schlosser and the Problem of Universal History;" and a talk recalling his early years as a student of Boeckh, Jakob Grimm, Mommsen, Ranke, and Ritter. It also contains the important historical essay "The Eighteenth Century and the Historical World," in which Dilthey reexamines the Enlightenment to show its significant contributions to the rise of historical consciousness.
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