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Polymorphisms in the vitamin D receptor gene are associated with reduced rate of sputum culture conversion in multidrug-resistant tuberculosis patients in South Africa.

ABSTRACT: Background: Vitamin D modulates the inflammatory and immune response to tuberculosis (TB) and also mediates the induction of the antimicrobial peptide cathelicidin. Deficiency of 25-hydroxyvitamin D and single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene may increase the risk of TB disease and decrease culture conversion rates in drug susceptible TB. Whether these VDR SNPs are found in African populations or impact multidrug-resistant (MDR) TB treatment has not been established. We aimed to determine if SNPs in the VDR gene were associated with sputum culture conversion among a cohort of MDR TB patients in South Africa.

Methods: We conducted a prospective cohort study of adult MDR TB patients receiving second-line TB treatment in KwaZulu-Natal province. Subjects had monthly sputum cultures performed. In a subset of participants, whole blood samples were obtained for genomic analyses. Genomic DNA was extracted and genotyped with Affymetrix Axiom Pan-African Array. Cox proportional models were used to determine the association between VDR SNPs and rate of culture conversion.

Results: Genomic analyses were performed on 91 MDR TB subjects enrolled in the sub-study; 60% were female and median age was 35 years (interquartile range [IQR] 29-42). Smoking was reported by 21% of subjects and most subjects had HIV (80%), were smear negative (57%), and had cavitary disease (55%). Overall, 87 (96%) subjects initially converted cultures to negative, with median time to culture conversion of 57 days (IQR 17-114). Of 121 VDR SNPs examined, 10 were significantly associated (p<0.01) with rate of sputum conversion in multivariable analyses. Each additional risk allele on SNP rs74085240 delayed culture conversion significantly (adjusted hazard ratio 0.30, 95% confidence interval 0.14-0.67).

Conclusions: Polymorphisms in the VDR gene were associated with rate of sputum culture conversion in MDR TB patients in this high HIV prevalence setting in South Africa.

SUBMITTER: Magee MJ

PROVIDER: S-EPMC5507304 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Polymorphisms in the vitamin D receptor gene are associated with reduced rate of sputum culture conversion in multidrug-resistant tuberculosis patients in South Africa.

Magee Matthew J MJ Sun Yan V YV Brust James C M JCM Shah N Sarita NS Ning Yuming Y Allana Salim S Campbell Angela A Hui Qin Q Mlisana Koleka K Moodley Pravi P Gandhi Neel R NR

PloS one 20170710 7

<h4>Background</h4>Vitamin D modulates the inflammatory and immune response to tuberculosis (TB) and also mediates the induction of the antimicrobial peptide cathelicidin. Deficiency of 25-hydroxyvitamin D and single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene may increase the risk of TB disease and decrease culture conversion rates in drug susceptible TB. Whether these VDR SNPs are found in African populations or impact multidrug-resistant (MDR) TB treatment has not bee ...[more]

PMID: 28700743

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Project description:Both vitamin D deficiency and genetic variants in the vitamin D receptor (VDR) have been reported to associate with delayed response to intensive-phase therapy for pulmonary tuberculosis. Studies investigating the influence of genetic variants in vitamin D binding protein (DBP) and vitamin D 25-hydroxylase (CYP2R1) on vitamin D status and response to antituberculous therapy are lacking.We conducted a longitudinal study in 260 patients initiating treatment for smear-positive pulmonary tuberculosis in Lahore, Pakistan. Vitamin D status and genotypes for polymorphisms in VDR (rs2228570, rs731236, rs1544410), DBP (rs7041, rs4588) and CYP2R1 (rs2060793, rs10500804, rs10766197) were determined at baseline. Sputum smear microscopy was performed at 2, 4, 6 and 8 weeks, and time to sputum smear conversion was estimated for each participant. Analyses were conducted to determine demographic, clinical and genetic determinants of baseline vitamin D status and time to sputum smear conversion.Profound vitamin D deficiency (serum 25[OH]D < 25 nmol/L) was highly prevalent at TB diagnosis (present in 54 % of patients), and was independently associated with female vs. male sex (adjusted OR 2.60, 95 % CI 1.50 to 4.52, P = 0.001), recruitment in October to March inclusive (adjusted OR 1.75, 95 % CI 1.00 to 3.04, P = 0.047) and bilateral vs. unilateral disease (adjusted OR 1.89, 95 % CI 1.49 to 4.52 P = 0.025). Profound vitamin D deficiency was also independently associated with impaired response to antituberculous therapy (median time to sputum smear conversion 22.5 vs. 7.5 days for patients with serum 25[OH]D < 25 nmol/L vs. ? 25 nmol/L, respectively; aHR 4.36, 95 % CI 3.25 to 6.65, P < 0.001). No polymorphisms in VDR, CYP2R1 and DBP studied associated with either baseline vitamin D status or time to sputum smear conversion.Profound vitamin D deficiency is very common among TB patients in Lahore, Pakistan, and is independently associated with significantly delayed sputum smear conversion. Polymorphisms in VDR, CYP2R1 and DBP did not associate with baseline vitamin D status or response to intensive-phase treatment in this patient group.

Project description:BackgroundTuberculosis Trials Consortium Study 28, was a double blind, randomized, placebo-controlled, phase 2 clinical trial examining smear positive pulmonary Mycobacterium tuberculosis. Over the course of intensive phase therapy, patients from African sites had substantially delayed and lower rates of culture conversion to negative in liquid media compared to non-African patients. We explored potential explanations of this finding.MethodsIn TBTC Study 28, protocol-correct patients (n = 328) provided spot sputum specimens for M. tuberculosis culture in liquid media, at baseline and weeks 2, 4, 6 and 8 of study therapy. We compared sputum culture conversion for African and non-African patients stratified by four baseline measures of disease severity: AFB smear quantification, extent of disease on chest radiograph, cavity size and the number of days to detection of M. tuberculosis in liquid media using the Kaplan-Meier product-limit method. We evaluated specimen processing and culture procedures used at 29 study laboratories serving 27 sites.ResultsAfrican TB patients had more extensive disease at enrollment than non-African patients. However, African patients with the least disease by the 4 measures of disease severity had conversion rates on liquid media that were substantially lower than conversion rates in non-African patients with the greatest extent of disease. HIV infection, smoking and diabetes did not explain delayed conversion in Africa. Some inter-site variation in laboratory processing and culture procedures within accepted practice for clinical diagnostic laboratories was found.ConclusionsCompared with patients from non-African sites, African patients being treated for TB had delayed sputum culture conversion and lower sputum conversion rates in liquid media that were not explained by baseline severity of disease, HIV status, age, smoking, diabetes or race. Further investigation is warranted into whether modest variation in laboratory processes substantially influences the efficacy outcomes of phase 2 TB treatment trials or if other factors (e.g., nutrition, host response) are involved.Trial registrationClinicalTrials.gov NCT00144417.

Dataset Information

Polymorphisms in the vitamin D receptor gene are associated with reduced rate of sputum culture conversion in multidrug-resistant tuberculosis patients in South Africa.

Publications

Polymorphisms in the vitamin D receptor gene are associated with reduced rate of sputum culture conversion in multidrug-resistant tuberculosis patients in South Africa.

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