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      Association of Vitamin D Receptor BsmI Gene Polymorphism with Risk of Tuberculosis: A Meta-Analysis of 15 Studies

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          Abstract

          Background

          Genetic variations in vitamin D receptor (VDR) may contribute to tuberculosis (TB) risk. Many studies have investigated the association between VDR BsmI gene polymorphism and TB risk, but yielded inconclusive results.

          Methodology/Principal Findings

          We performed a comprehensive meta-analysis of 15 publications with a total of 2309 cases and 3568 controls. We assessed the strength of the association between VDR BsmI gene polymorphism and TB risk and performed sub-group analyses by ethnicity, sample size and Hardy–Weinberg equilibrium (HWE). We found a statistically significant correlation between VDR BsmI gene polymorphism and decreased TB risk in four comparison models: allele model (b vs. B: OR = 0.78, 95% CI = 0.67, 0.89; P heterogeneity = 0.004), homozygote model (bb vs. BB: OR = 0.61, 95% CI = 0.43, 0.87; P heterogeneity = 0.001), recessive model (bb vs. Bb+BB: OR = 0.70, 95% CI = 0.56, 0.88; P heterogeneity = 0.005) and dominant model (bb+Bb vs. BB: OR = 0.77, 95% CI = 0.61, 0.97; P heterogeneity = 0.010), especially in studies based on Asian population. Sub-group analyses also revealed that there was a statistically decreased TB risk in “small” studies (<500 participants) and studies with P HWE>0.5. Meta-regression and stratification analysis both showed that the ethnicity and sample size contributed to heterogeneity.

          Conclusions

          This meta-analysis suggests that VDR BsmI gene polymorphism is associated with a significant decreased TB risk, especially in Asian population.

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          Most cited references35

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          Genetics and biology of vitamin D receptor polymorphisms.

          The vitamin D endocrine system is involved in a wide variety of biological processes including bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation. Variations in this endocrine system have, thus, been linked to several common diseases, including osteoarthritis (OA), diabetes, cancer, cardiovascular disease, and tuberculosis. Evidence to support this pleiotropic character of vitamin D has included epidemiological studies on circulating vitamin D hormone levels, but also genetic epidemiological studies. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and have therefore gained much interest. DNA sequence variations, which occur frequently in the population, are referred to as "polymorphisms" and can have modest and subtle but true biological effects. Their abundance in the human genome as well as their high frequencies in the human population have made them targets to explain variation in risk of common diseases. Recent studies have indicated many polymorphisms to exist in the vitamin D receptor (VDR) gene, but the influence of VDR gene polymorphisms on VDR protein function and signaling is largely unknown. So far, three adjacent restriction fragment length polymorphisms for BsmI, ApaI, and TaqI, respectively, at the 3' end of the VDR gene have been the most frequently studied. Because these polymorphisms are probably nonfunctional, linkage disequilibrium with one or more truly functional polymorphisms elsewhere in the VDR gene is assumed to explain the associations observed. Research is therefore focussed on documenting additional polymorphisms across the VDR gene to verify this hypothesis and on trying to understand the functional consequences of the variations. Substantial progress has been made that will deepen our understanding of variability in the vitamin D endocrine system and might find applications in risk assessment of disease and in predicting response-to-treatment.
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            Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene.

            The functional significance of two unlinked human vitamin D receptor (hVDR) gene polymorphisms was evaluated in twenty human fibroblast cell lines. Genotypes at both a Fok I restriction site (F/f) in exon II and a singlet (A) repeat in exon IX (L/S) were determined, and relative transcription activities of endogenous hVDR proteins were measured using a transfected, 1,25-dihydroxyvitamin D(3)-responsive reporter gene. Observed activities ranged from 2--100-fold induction by hormone, with higher activity being displayed by the F and the L biallelic forms. Only when genotypes at both sites were considered simultaneously did statistically significant differences emerge. Moreover, the correlation between hVDR activity and genotype segregated further into clearly defined high and low activity groups with similar genotypic distributions. These results not only demonstrate functional relevance for both the F/f and L/S common polymorphisms in hVDR, but also provide novel evidence for a third genetic variable impacting receptor potency.
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              Racial differences in susceptibility to infection by Mycobacterium tuberculosis.

              The prevalence of tuberculosis among blacks is known to be about twice that among whites. When we looked at infection rates among the initially tuberculin-negative residents of 165 racially integrated nursing homes in Arkansas, we were stimulated to investigate whether this difference could be due in part to racial differences in susceptibility to Mycobacterium tuberculosis infection. A new infection was defined by an increase of greater than or equal to 12 mm of induration after a tuberculin skin test (5 tuberculin units) administered at least 60 days after a negative two-step test. On repeat skin testing of the 25,398 initially tuberculin-negative nursing home residents, we found that 13.8 percent of the blacks and only 7.2 percent of the whites had evidence of a new infection (relative risk, 1.9; 95 percent confidence interval, 1.7 to 2.1). Blacks were infected more frequently, regardless of the race of the source patient. In homes with a single source patient who was white, 17.4 percent of the black and 11.7 percent of the white residents became infected (relative risk, 1.5; 95 percent confidence interval, 1.2 to 1.9); in homes with a single source patient who was black, 12.4 percent of the black and 7.7 percent of the white residents became infected (relative risk, 1.6; 95 percent confidence interval, 1.2 to 2.1). However, there was no racial difference in the percentage of residents who had recently converted to positive status who, in the absence of preventive therapy, were later found to have clinical tuberculosis (blacks, 11.5 percent; whites, 10.6 percent). Data from three outbreaks of tuberculosis in two prisons also showed that blacks have about twice the relative risk of whites of becoming infected with M. tuberculosis. We conclude that blacks are more readily infected by M. tuberculosis than are whites. The data also suggest that susceptibility to M. tuberculosis infection varies independently of the factors governing the progression to clinical disease.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                25 June 2013
                : 8
                : 6
                : e66944
                Affiliations
                [1 ]Department of Pharmacy, Changzhou Third People’s Hospital, Changzhou, China
                [2 ]College of Pharmacy, Soochow University, Suzhou, China
                [3 ]The Fourth Clinical College of Nanjing Medical University, Nanjing, China
                [4 ]Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu Province, Nanjing, China
                [5 ]Department of Bio-statistics, Georgia Health Science University, Augusta, Georgia, United States of America
                [6 ]Department of Pharmacy, Changzhou First People’s Hospital, Changzhou, China
                [7 ]Department of Pulmonary Tuberculosis, Changzhou Third People’s Hospital, Changzhou, China
                Fundacion Huesped, Argentina
                Author notes

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

                Conceived and designed the experiments: YJW XY LX FLT. Performed the experiments: YJW XY XXW YZY ZXZ SMZ LX FLT. Analyzed the data: YJW XY XXW. Contributed reagents/materials/analysis tools: YJW XY XXW MTQ. Wrote the paper: YJW XY XXW. Access to full-text article: YJW XY.

                Article
                PONE-D-13-12940
                10.1371/journal.pone.0066944
                3692555
                23825591
                4b0d72ec-c666-4bb1-8adb-423f104056a6
                Copyright @ 2013

                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.

                History
                : 29 March 2013
                : 12 May 2013
                Page count
                Pages: 8
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Biology
                Genetics
                Population Genetics
                Genetic Polymorphism
                Population Biology
                Population Genetics
                Genetic Polymorphism
                Medicine
                Clinical Research Design
                Meta-Analyses
                Epidemiology
                Genetic Epidemiology
                Infectious Disease Epidemiology
                Infectious Diseases
                Bacterial Diseases
                Tuberculosis
                Non-Clinical Medicine
                Health Care Policy
                Health Risk Analysis

                Uncategorized
                Uncategorized

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