Abstract
BackgroundA 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.MethodsWe 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.ResultsThe 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 (ORinteraction = 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.ConclusionBoth 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.
Highlights
A variety of abnormalities in vitamin D metabolism have been reported in patients with active tuberculosis
After informed consent was obtained from all participants, questionnaires were used to collect demographic data
The distribution of marital status was significantly different (P < 0.001). The proportion of those who had ever smoked in the cases was slightly higher than that in the controls (42.6% vs. 39.0%), while the percentage of those who drank alcohol was slightly lower in the cases than in the controls (26.2% vs. 29.7%), there was not a significant difference (Table 2)
Summary
A variety of abnormalities in vitamin D metabolism have been reported in patients with active tuberculosis. Factors related to the risk of TB include low socioeconomic status, poor nutrition, traditional/cultural traits, tobacco smoking, contacts with sputum smear-positive index patients, and genetic susceptibility [4,5,6,7,8]. Studies have reported that hypovitaminosis D results in lower antimycobacterial immunity [10, 11] and is related to increased risk of TB [12, 13]. Some studies have shown that vitamin D supplementation during the intensive phase of antimicrobial treatment can increase sputum negative conversion rates [15, 16]. Confounding factors and reverse causation may partly explain the inconsistencies [18], but individual variations in vitamin D metabolism and related variations in immune responses should not be neglected
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