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      Alleles of HLA-DRB1*04 Associated with Pulmonary Tuberculosis in Amazon Brazilian Population

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          Abstract

          Immunogenetic host factors are associated with susceptibility or protection to tuberculosis (TB). Strong associations of HLA class II genes with TB are reported. We analyzed the HLA-DRB1*04 alleles to identify subtypes associated with pulmonary TB and their interaction with risk factors such as alcohol, smoking, and gender in 316 pulmonary TB patients and 306 healthy individuals from the Brazilian Amazon. The HLA-DRB1*04 was prevalent in patients with pulmonary TB ( p<0.0001; OR = 2.94; 95% CI = 2.12 to 4.08). Direct nucleotide sequencing of DRB1 exon 2 identified nine subtypes of HLA-DRB1*04. The subtype HLA-DRB1*04: 11: 01 ( p = 0.0019; OR = 2.23; 95% CI = 1.34 to 3.70) was associated with susceptibility to pulmonary TB while DRB1*04: 07: 01 ( p<0.0001; OR = 0.02; 95% CI = 0.001 to 0.33) to protection. Notably, the interaction between alcohol and HLA-DRB1*04: 11: 01 increased the risk for developing pulmonary TB ( p = 0.0001; OR = 51.3; 95% CI = 6.81 to 386). Multibacillary pulmonary TB, the clinical presentation of disease transmission, was strongly associated with interaction to alcohol ( p = 0.0026; OR = 11.1; 95% CI = 3.99 to 30.9), HLA-DRB1*04: 11: 01 ( p = 0.0442; OR = 2.01; 95% CI = 1.03 to 3.93) and DRB1*04: 92 ( p = 0.0112; OR = 8.62; 95% CI = 1.63 to 45.5). These results show that HLA-DRB1*04 are associated with pulmonary TB. Interestingly, three subtypes, DRB1*04: 07: 01, DRB1*04: 11: 01 and DRB1*04: 92 of the HLA-DRB1*04 could be potential immunogenetic markers that may help to explain mechanisms involved in disease development.

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          Most cited references 55

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          DNA sequencing with chain-terminating inhibitors.

          A new method for determining nucleotide sequences in DNA is described. It is similar to the "plus and minus" method [Sanger, F. & Coulson, A. R. (1975) J. Mol. Biol. 94, 441-448] but makes use of the 2',3'-dideoxy and arabinonucleoside analogues of the normal deoxynucleoside triphosphates, which act as specific chain-terminating inhibitors of DNA polymerase. The technique has been applied to the DNA of bacteriophage varphiX174 and is more rapid and more accurate than either the plus or the minus method.
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            The IPD and IMGT/HLA database: allele variant databases

            The Immuno Polymorphism Database (IPD) was developed to provide a centralized system for the study of polymorphism in genes of the immune system. Through the IPD project we have established a central platform for the curation and publication of locus-specific databases involved either directly or related to the function of the Major Histocompatibility Complex in a number of different species. We have collaborated with specialist groups or nomenclature committees that curate the individual sections before they are submitted to IPD for online publication. IPD consists of five core databases, with the IMGT/HLA Database as the primary database. Through the work of the various nomenclature committees, the HLA Informatics Group and in collaboration with the European Bioinformatics Institute we are able to provide public access to this data through the website http://www.ebi.ac.uk/ipd/. The IPD project continues to develop with new tools being added to address scientific developments, such as Next Generation Sequencing, and to address user feedback and requests. Regular updates to the website ensure that new and confirmatory sequences are dispersed to the immunogenetics community, and the wider research and clinical communities.
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              Allele frequency net 2015 update: new features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations

              It has been 12 years since the Allele Frequency Net Database (AFND; http://www.allelefrequencies.net) was first launched, providing the scientific community with an online repository for the storage of immune gene frequencies in different populations across the world. There have been a significant number of improvements from the first version, making AFND a primary resource for many clinical and scientific areas including histocompatibility, immunogenetics, pharmacogenetics and anthropology studies, among many others. The most widely used part of AFND stores population frequency data (alleles, genes or haplotypes) related to human leukocyte antigens (HLA), killer-cell immunoglobulin-like receptors (KIR), major histocompatibility complex class I chain-related genes (MIC) and a number of cytokine gene polymorphisms. AFND now contains >1400 populations from more than 10 million healthy individuals. Here, we report how the main features of AFND have been updated to include a new section on ‘HLA epitope’ frequencies in populations, a new section capturing the results of studies identifying HLA associations with adverse drug reactions (ADRs) and one for the examination of infectious and autoimmune diseases associated with KIR polymorphisms—thus extending AFND to serve a new user base in these growing areas of research. New criteria on data quality have also been included.
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                Author and article information

                Affiliations
                [1 ]Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas (UFAM), Manaus, Amazonas, Brasil
                [2 ]Laboratório de Micobacteriologia, Instituto Nacional de Pesquisas da Amazônia (INPA), Manaus, Amazonas, Brasil
                [3 ]Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas (FCF), Manaus, Amazonas, Brasil
                [4 ]Policlínica Cardoso Fontes, Manaus, Amazonas, Brasil
                [5 ]Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT/HVD), Manaus, Amazonas, Brasil
                [6 ]Universidade Nilton Lins, Manaus, Amazonas, Brasil
                Charite Universitätsmedizin Berlin, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: DSL AS MMO IAA. Performed the experiments: DSL MMO MPS CMMS VAA. Analyzed the data: DSL ALB AS RR. Contributed reagents/materials/analysis tools: AS MMO. Wrote the paper: DSL AS RR MMO ALB. Designed primers: DSL.

                ‡ These authors also contributed equally to this work.

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                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                22 February 2016
                2016
                : 11
                : 2
                26901036 4764689 10.1371/journal.pone.0147543 PONE-D-15-33949
                © 2016 Souza de Lima et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                Funding
                The work was supported by the PPSUS – Programa de Pesquisa para o SUS: Gestão compartilhada em Saúde, FAPEAM – Fundação de Amparo à Pesquisa do Estado do Amazonas (Edital 007/2009), PIPT—Programa Integrado de Pesquisa Científica e Tecnológica, FAPEAM – Fundação de Amparo à Pesquisa do Estado do Amazonas (Edital 009/2007) and MCT – Ministério da Ciência e Tecnologia/CNPq – Conselho Nacional de Desenvolvimento Científico e Tecnológico, Universal, Processo No. 473484/2007-2 (Edital MCT/CNPq 15/2007).
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