Vitamin D and the promoter methylation of its metabolic pathway genes in association with the risk and prognosis of tuberculosis

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Abstract

Background

A variety of abnormalities in vitamin D metabolism have been reported in patients with active tuberculosis. However, intervention trials have produced inconsistent results. We hypothesized that genetic and epigenetic changes in the key genes of the vitamin D metabolic pathway may partly explain the differences between studies.

Methods

We performed a case-control study followed by a prospective cohort study. We recruited 122 patients with pulmonary tuberculosis and 118 healthy controls. The serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were measured. The methylation of the promoter regions of key genes in the vitamin D metabolic pathway (CYP24A1, CYP27A1, CYP27B1, CYP2R1, and VDR) was detected using the Illumina MiSeq platform. The specific methylation profiles were examined as epigenetic biomarkers. The sensitivity, specificity, and receiver operating characteristic (ROC) curves were used to estimate the predictive value of the biomarkers.

Results

The baseline serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations in the cases were significantly lower than those in the controls (51.60 ± 27.25 nmol/L vs. 117.50 ± 75.50 nmol/L, Z = − 8.515, P < 0.001; 82.63 ± 51.43 pmol/L vs. 94.02 ± 49.26 pmol/L, Z = − 2.165, P = 0.03). We sequenced 310 CpG sites in five candidate genes. After Bonferroni correction, there were 55 differentially methylated CpG sites between cases and controls; 41.5% were in the CYP27B1 gene, 31.7% were in the CYP24A1 gene, 14.7% were in the VDR gene, and 12.3% were in the CYP27A1 gene. When we designated the CpG sites that remained significant after the Bonferroni correction as the biomarkers, the area under the curve (AUC) for the cumulative methylation was 0.810 (95% CI 0.754–0.866). There was an interaction between CYP27A1 methylation level and 1,25-dihydroxyvitamin D concentration associated with the risk of TB (OR _interaction = 4.11, 95% CI 1.26–13.36, P = 0.019). The serum 1,25-dihydroxyvitamin D concentration at the end of the intensive treatment stage was related to a patient’s prognosis ( P = 0.008). There were 23 CpG sites that were individually related to the treatment outcomes, but the relationships were not significant after the Bonferroni correction.

Conclusion

Both serum vitamin D concentrations and the methylation levels of key genes in the vitamin D metabolic pathway are related to the risk and prognosis of tuberculosis.

Electronic supplementary material

The online version of this article (10.1186/s13148-018-0552-6) contains supplementary material, which is available to authorized users.

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To explore the association between low serum vitamin D and risk of active tuberculosis in humans. Systematic review and meta-analysis. Observational studies published between 1980 and July 2006 (identified through Medline) that examined the association between low serum vitamin D and risk of active tuberculosis. For the review, seven papers were eligible from 151 identified in the search. The pooled effect size in random effects meta-analysis was 0.68 with 95% CI 0.43-0.93. This 'medium to large' effect represents a probability of 70% that a healthy individual would have higher serum vitamin D level than an individual with tuberculosis if both were chosen at random from a population. There was little heterogeneity between the studies. Low serum vitamin D levels are associated with higher risk of active tuberculosis. Although more prospectively designed studies are needed to firmly establish the direction of this association, it is more likely that low body vitamin D levels increase the risk of active tuberculosis. In view of this, the potential role of vitamin D supplementation in people with tuberculosis and hypovitaminosis D-associated conditions like chronic kidney disease should be evaluated.

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Blood biomarkers of vitamin D status.

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In the past quarter century, more than 50 metabolites of vitamin D have been described. To date, only a few of these have been quantified in blood, but this has widened our understanding of the pathologic role that altered vitamin D metabolism plays in the development of diseases of calcium homeostasis. Currently, awareness is growing of the prevalence of vitamin D insufficiency in the general population in association with an increased risk of several diseases. However, for many researchers, it is not clear which vitamin D metabolites should be quantified and what the information gained from such an analysis tells us. Only 2 metabolites, namely, 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D], have received the greatest attention. Of these, the need for measuring serum 1,25(OH)2D is limited, and this metabolite should therefore not be considered as part of the standard vitamin D testing regimen. On the other hand, serum 25(OH)D provides the single best assessment of vitamin D status and thus should be the only vitamin D assay typically performed. Currently, numerous formats exist for measuring serum 25(OH)D concentrations, each with its own advantages and disadvantages. This article reviews the currently available methods for serum 25(OH)D quantitation and considers important issues such as whether both the D2 and the D3 forms of the vitamin should be assayed, whether total or free concentrations are most important, and what measures should be taken to ensure the fidelity of the measurements.

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Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial.

Christian Wejse, Victor F. Gomes, Paulo Rabna … (2009)

Vitamin D has been shown to be involved in the host immune response toward Mycobacterium tuberculosis. To test whether vitamin D supplementation of patients with tuberculosis (TB) improved clinical outcome and reduced mortality. We conducted a randomized, double-blind, placebo-controlled trial in TB clinics at a demographic surveillance site in Guinea-Bissau. We included 365 adult patients with TB starting antituberculosis treatment; 281 completed the 12-month follow-up. The intervention was 100,000 IU of cholecalciferol or placebo at inclusion and again 5 and 8 months after the start of treatment. The primary outcome was reduction in a clinical severity score (TBscore) for all patients with pulmonary TB. The secondary outcome was 12-month mortality. No serious adverse effects were reported; mild hypercalcemia was rare and present in both arms. Reduction in TBscore and sputum smear conversion rates did not differ among patients treated with vitamin D or placebo. Overall mortality was 15% (54 of 365) at 1 year of follow-up and similar in both arms (30 of 187 for vitamin D treated and 24 of 178 for placebo; relative risk, 1.19 [0.58-1.95]). HIV infection was seen in 36% (131 of 359): 21% (76 of 359) HIV-1, 10% (36 of 359) HIV-2, and 5% (19 of 357) HIV-1+2. Vitamin D does not improve clinical outcome among patients with TB and the trial showed no overall effect on mortality in patients with TB; it is possible that the dose used was insufficient. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN35212132).

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Author and article information

Contributors

Jianming Wang:

ORCID: http://orcid.org/0000-0002-9151-284X

86-25-86868438 , jmwang@njmu.edu.cn

Journal

Journal ID (nlm-ta): Clin Epigenetics

Journal ID (iso-abbrev): Clin Epigenetics

Title: Clinical Epigenetics

Publisher: BioMed Central (London )

ISSN (Print): 1868-7075

ISSN (Electronic): 1868-7083

Publication date (Electronic): 12 September 2018

Publication date PMC-release: 12 September 2018

Publication date Collection: 2018

Volume: 10

Electronic Location Identifier: 118

Affiliations

[1 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Department of Epidemiology, , School of Public Health, Nanjing Medical University, ; 101 Longmian Ave, Nanjing, 211166 People’s Republic of China

[2 ]Department of Preventive Health Care, People’s Hospital of Suzhou High-tech Zone, Suzhou, People’s Republic of China

[3 ]Department of Nursing, The First People’s Hospital of Yancheng City, Yancheng, People’s Republic of China

[4 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Key Laboratory of Infectious Diseases, , School of Public Health, Nanjing Medical University, ; Nanjing, People’s Republic of China

Author information

Jianming Wang http://orcid.org/0000-0002-9151-284X

Article

Publisher ID: 552

DOI: 10.1186/s13148-018-0552-6

PMC ID: 6136159

PubMed ID: 30208925

SO-VID: 1f334d42-5e20-43a7-bc88-671b2b03f76e

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 6 June 2018

Date accepted : 4 September 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81473027