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      Lack of association between polymorphism of IL-2 -330T/G and pulmonary tuberculosis among Caucasians

      research-article
      1 , 2 , 2
      Innate Immunity
      SAGE Publications
      IL-2, polymorphism, pulmonary tuberculosis, meta-analysis

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          Abstract

          This meta-analysis was conducted to assess the consistency and strength of the relationship between polymorphism of IL-2 -330T/G and susceptibility to pulmonary tuberculosis (TB). PubMed, Web of Knowledge and CNKI were searched to find eligible studies about the relationship between IL-2 -330T/G polymorphism and susceptibility to pulmonary TB. A total of eight studies comprising 971 cases and 1519 controls were grouped together for the purpose of elucidating the relationship between polymorphism of IL-2 -330T/G and pulmonary TB susceptibility. The allele model (G vs. T: odds ratio (OR) = 1.34; 95% confidence interval (CI) 1.05–1.71, P het = 0.001) and the recessive model (GG+GT vs. TT: OR = 1.60; 95% CI 1.08–2.38, P het = 0.0001) showed an increased risk of development of pulmonary TB. However, the homozygous model (GG vs. TT: OR = 1.74; 95% CI 0.98–3.09, P het = 0.0005) and the dominant model (GG vs. TT + TG: OR = 1.30; 95% CI = 0.80-2.14, P het =  0.001) failed to show an increased incidence of pulmonary TB. When analysis was stratified by ethnicity, no obvious associations were identified in the Caucasian subgroup under all four genetic models. Additionally, heterogeneity disappeared in the analysis of Caucasian subgroup. Our combined data suggested that there was no association between IL-2 -330T/G polymorphism and pulmonary TB among Caucasians.

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          Synthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approaches.

          The aim of the study was to consider statistical and methodological issues affecting the results of meta-analysis of genetic association studies for pertinent gene-disease associations. Although the basic statistical issues for performing meta-analysis are well described in the literature, there are remaining methodological issues. An analysis of our database and a literature review were performed to assess issues such as departure of Hardy-Weinberg equilibrium, genetic contrasts, sources of bias (replication validity, early extreme contradictory results, differential magnitude of effect in large versus small studies, and "racial" diversity), utility of cumulative and recursive cumulative meta-analyses. Gene-gene-environment interactions and methodological challenges of genome-wide association studies are discussed. Departures from Hardy-Weinberg equilibrium can be handled using sensitivity analysis or correction procedures. A spectrum of genetic models should be investigated in the absence of biological justification. Cumulative and recursive cumulative meta-analyses are useful to explore heterogeneity in risk effect in time. Exploration of bias leading to heterogeneity provides insight to postulated genetic effects. In the presence of bias, results should be interpreted with caution. Meta-analysis provides a robust tool to investigate contradictory results in genetic association studies by estimating population-wide effects of genetic risk factors in diseases and explaining sources of bias and heterogeneity.
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            Rational inferences about departures from Hardy-Weinberg equilibrium.

            Previous studies have explored the use of departure from Hardy-Weinberg equilibrium (DHW) for fine mapping Mendelian disorders and for general fine mapping. Other studies have used Hardy-Weinberg tests for genotyping quality control. To enable investigators to make rational decisions about whether DHW is due to genotyping error or to underlying biology, we developed an analytic framework and software to determine the parameter values for which DHW might be expected for common diseases. We show analytically that, for a general disease model, the difference between population and Hardy-Weinberg expected genotypic frequencies (delta) at the susceptibility locus is a function of the susceptibility-allele frequency (q), heterozygote relative risk (beta), and homozygote relative risk (gamma). For unaffected control samples, is a function of risk in nonsusceptible homozygotes (alpha), the population prevalence of disease (KP), q, beta, and gamma. We used these analytic functions to calculate and the number of cases or controls needed to detect DHW for a range of genetic models consistent with common diseases (1.1 < or = gamma < or = 10 and 0.005 < or = KP < or = 0.2). Results suggest that significant DHW can be expected in relatively small samples of patients over a range of genetic models. We also propose a goodness-of-fit test to aid investigators in determining whether a DHW observed in the context of a case-control study is consistent with a genetic disease model. We illustrate how the analytic framework and software can be used to help investigators interpret DHW in the context of association studies of common diseases.
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              Tuberculosis Susceptibility and Vaccine Protection Are Independently Controlled by Host Genotype

              ABSTRACT The outcome of Mycobacterium tuberculosis infection and the immunological response to the bacillus Calmette-Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of BCG has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individual mice, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly diverse inbred mouse strains, consisting of the founders and recombinant progeny of the “Collaborative Cross” project. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically identical individuals and the quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects: the animals displayed a broad range of susceptibility to M. tuberculosis, differed in their immunological responses to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. M. tuberculosis susceptibility varied between lines, from extreme sensitivity to progressive M. tuberculosis clearance. Similarly, only a minority of the genotypes was protected by vaccination. The efficacy of BCG was genetically separable from susceptibility to M. tuberculosis, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic diversity in determining BCG efficacy and provide a new resource to rationally develop more broadly efficacious vaccines.
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                Author and article information

                Journal
                Innate Immun
                Innate Immun
                INI
                spini
                Innate Immunity
                SAGE Publications (Sage UK: London, England )
                1753-4259
                1753-4267
                6 January 2020
                July 2020
                : 26
                : 5
                : 398-402
                Affiliations
                [1 ]Department of Respiratory Medicine, Nanjing Hospital of Traditional Chinese Medicine/Third Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, PR China
                [2 ]Department of Respiratory Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, PR China
                Author notes
                [*]Shi Chen and Jia Zhu, Department of Respiratory Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, PR China. Emails: cshonest1981@ 123456sina.com ; jsnjzj@ 123456163.com
                Author information
                https://orcid.org/0000-0002-6909-7459
                Article
                10.1177_1753425919891579
                10.1177/1753425919891579
                7903529
                31906759
                9eaa1f62-5854-4962-a960-45864114dda1
                © The Author(s) 2020

                Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 3 October 2019
                : 6 November 2019
                Categories
                Original Articles
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                Immunology
                il-2,polymorphism,pulmonary tuberculosis,meta-analysis
                Immunology
                il-2, polymorphism, pulmonary tuberculosis, meta-analysis

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