DHCR7 mutations linked to higher vitamin D status allowed early human migration to Northern latitudes

PMCID: PMC3708787This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Inflammation-mediated tissue damage in pulmonary tuberculosis and host-directed therapeutic strategies.

Treatment of tuberculosis (TB) involves the administration of anti-mycobacterial drugs for several months. The emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb, the causative agent) together with increased disease severity in people with co-morbidities such as diabetes mellitus and HIV have hampered efforts to reduce case fatality. In severe disease, TB pathology is largely attributable to over-exuberant host immune responses targeted at controlling bacterial replication. Non-resolving inflammation driven by host pro-inflammatory mediators in response to high bacterial load leads to pulmonary pathology including cavitation and fibrosis. The need to improve clinical outcomes and reduce treatment times has led to a two-pronged approach involving the development of novel antimicrobials as well as host-directed therapies (HDT) that favourably modulate immune responses to Mtb. HDT strategies incorporate aspects of immune modulation aimed at downregulating non-productive inflammatory responses and augmenting antimicrobial effector mechanisms to minimise pulmonary pathology and accelerate symptom resolution. HDT in combination with existing antimycobacterial agents offers a potentially promising strategy to improve the long-term outcome for TB patients. In this review, we describe components of the host immune response that contribute to inflammation and tissue damage in pulmonary TB, including cytokines, matrix metalloproteinases, lipid mediators, and neutrophil extracellular traps. We then proceed to review HDT directed at these pathways

Tuberculosis incidence correlates with sunshine : an ecological 28-year time series study

Birmingham is the largest UK city after London, and central Birmingham has an annual tuberculosis incidence of 80 per 100,000. We examined seasonality and sunlight as drivers of tuberculosis incidence. Hours of sunshine are seasonal, sunshine exposure is necessary for the production of vitamin D by the body and vitamin D plays a role in the host response to tuberculosis. Methods: We performed an ecological study that examined tuberculosis incidence in Birmingham from Dec 1981 to Nov 2009, using publicly-available data from statutory tuberculosis notifications, and related this to the seasons and hours of sunshine (UK Meteorological Office data) using unmeasured component models. Results: There were 9,739 tuberculosis cases over the study period. There was strong evidence for seasonality, with notifications being 24.1% higher in summer than winter (p<0.001). Winter dips in sunshine correlated with peaks in tuberculosis incidence six months later (4.7% increase in incidence for each 100 hours decrease in sunshine, p<0.001). Discussion and Conclusion: A potential mechanism for these associations includes decreased vitamin D levels with consequent impaired host defence arising from reduced sunshine exposure in winter. This is the longest time series of any published study and our use of statutory notifications means this data is essentially complete. We cannot, however, exclude the possibility that another factor closely correlated with the seasons, other than sunshine, is responsible. Furthermore, exposure to sunlight depends not only on total hours of sunshine but also on multiple individual factors. Our results should therefore be considered hypothesis-generating. Confirmation of a potential causal relationship between winter vitamin D deficiency and summer peaks in tuberculosis incidence would require a randomized-controlled trial of the effect of vitamin D supplementation on future tuberculosis incidence

Vitamin D and tuberculosis: where next?

"This is the peer reviewed version of the following article:Susanna, B., et al. "Vitamin D and tuberculosis:where next?" Journal of Internal Medicine 0(ja).which has been published in final form at doi: 10.1111/joim.12777 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.SB and PB receive support from the Swedish Research Council (VR) and the Swedish Heart and Lung Foundation (HLF). ARM is supported by the Higher Education Funding Council for England

Vitamin D for the management of asthma

Background Several clinical trials of vitamin D to prevent asthma exacerbation and improve asthma control have been conducted in children and adults, but a meta-analysis restricted to double-blind, randomised, placebo-controlled trials of this intervention is lacking. Objectives To evaluate the efficacy of administration of vitamin D and its hydroxylated metabolites in reducing the risk of severe asthma exacerbations (defined as those requiring treatment with systemic corticosteroids) and improving asthma symptom control. Search methods We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies in order to identify additional trials. Date of last search: January 2016. Selection criteria Double-blind, randomised, placebo-controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk or asthma symptom control or both. Data collection and analysis Two review authors independently applied study inclusion criteria, extracted the data, and assessed risk of bias. We obtained missing data from the authors where possible. We reported results with 95% confidence intervals (CIs). Main results We included seven trials involving a total of 435 children and two trials involving a total of 658 adults in the primary analysis. Of these, one trial involving 22 children and two trials involving 658 adults contributed to the analysis of the rate of exacerbations requiring systemic corticosteroids. Duration of trials ranged from four to 12 months, and the majority of participants had mild to moderate asthma. Administration of vitamin D reduced the rate of exacerbations requiring systemic corticosteroids (rate ratio 0.63, 95% CI 0.45 to 0.88; 680 participants; 3 studies; high-quality evidence), and decreased the risk of having at least one exacerbation requiring an emergency department visit or hospitalisation or both (odds ratio (OR) 0.39, 95% CI 0.19 to 0.78; number needed to treat for an additional beneficial outcome, 27; 963 participants; 7 studies; high-quality evidence). There was no effect of vitamin D on % predicted forced expiratory volume in one second (mean difference (MD) 0.48, 95% CI -0.93 to 1.89; 387 participants; 4 studies; high-quality evidence) or Asthma Control Test scores (MD -0.08, 95% CI -0.70 to 0.54; 713 participants; 3 studies; high-quality evidence). Administration of vitamin D did not influence the risk of serious adverse events (OR 1.01, 95% CI 0.54 to 1.89; 879 participants; 5 studies; moderate-quality evidence). One trial comparing low-dose versus high-dose vitamin D reported two episodes of hypercalciuria, one in each study arm. No other study reported any adverse event potentially attributable to administration of vitamin D. No participant in any included trial suffered a fatal asthma exacerbation. We did not perform a subgroup analysis to determine whether the effect of vitamin D on risk of severe exacerbation was modified by baseline vitamin D status, due to unavailability of suitably disaggregated data. We assessed two trials as being at high risk of bias in at least one domain; neither trial contributed data to the analysis of the outcomes reported above. Authors' conclusions Meta-analysis of a modest number of trials in people with predominantly mild to moderate asthma suggests that vitamin D is likely to reduce both the risk of severe asthma exacerbation and healthcare use. It is as yet unclear whether these effects are confined to people with lower baseline vitamin D status; further research, including individual patient data meta-analysis of existing datasets, is needed to clarify this issue. Children and people with frequent severe asthma exacerbations were under-represented; additional primary trials are needed to establish whether vitamin D can reduce the risk of severe asthma exacerbation in these groups

Vitamin D deficiency associates with susceptibility to tuberculosis in Pakistan, but polymorphisms in VDR, DBP and CYP2R1 do not

Background: Single nucleotide polymorphisms (SNPs) in the genes encoding the vitamin D receptor (VDR) and the vitamin D binding protein (DBP) have been reported to modify the influence of vitamin D deficiency on susceptibility to active tuberculosis (TB) in the UK, but this phenomenon has not been investigated in settings with a high TB burden. SNPs in CYP2R1, which encodes a vitamin D 25-hydroxylase enzyme, are known to influence vitamin D status, but their potential role in determining susceptibility to TB has not previously been investigated in any setting. Method: We conducted a case–control study in 260 pulmonary TB patients and 112 controls recruited in Lahore, Pakistan. Analyses were conducted to test for main effects of vitamin D status and SNPs in VDR (rs731236, rs2228570 and rs1544410), DBP (rs7041 and rs4588) and CYP2R1 (rs2060793, rs10500804 and rs10766197) on susceptibility to TB, and to investigate whether these SNPs modify the association between vitamin D status and disease susceptibility. Results: Profound vitamin D deficiency (serum 25-hydroxyvitamin D concentration ≤ 20 nmol/L) was common among TB patients (118/260, 45 %), and was independently associated with susceptibility to TB (adjusted odds ratio 1.87, 95 % CI 1.15 to 3.04, P = 0.01). However, none of the SNPs investigated associated with susceptibility to TB, either in main effects analysis, or in interaction with vitamin D status. Conclusion: Profound vitamin D deficiency was common among TB patients in this high-burden setting, and was independently associated with disease susceptibility. However, no statistically significant associations between SNPs in the vitamin D pathway and disease susceptibility was demonstrated.Higher Education Commission of Pakistan grant number BM7-139

Genotype-independent association between vitamin D deficiency and polycystic ovarian syndrome in Lahore, Pakistan.

Both vitamin D deficiency and single nucleotide polymorphisms (SNPs) in the gene encoding the vitamin D receptor (VDR) have been widely reported to associate with susceptibility to polycystic ovarian syndrome (PCOS). A case-control study was conducted to study the influence of vitamin D status and genotpye for 24 SNPs in four genes in the vitamin D pathway (VDR, DBP, CYP27B1, CYP24A1) on PCOS. Statistical analyses were conducted to identify phenotypic and genotypic factors associated with risk of PCOS and to test for interactions between genotype and vitamin D status. PCOS was independently associated with lower age, higher body mass index, lower waist-hip ratio, vitamin D deficiency (serum 25-hydroxyvitamin D concentration <10 ng/mL), lack of outdoor exercise, increased fasting glucose and a family history of PCOS in at least one first degree relative. No statistically significant association was observed between the genotype of any SNP investigated and risk of PCOS, either as a main effect or in interaction with vitamin D status. We report a strong and independent association between vitamin D deficiency and risk of PCOS in Pakistan, that was not modified by genetic variation in the vitamin D pathway

Ethnic Variation in Inflammatory Profile in Tuberculosis

PMCID: PMC3701709This 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