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

• Type of Material: Article
• Authors: Matthew Magee, Emory University; Yan Sun, Emory University; James C. M. Brust, Albert Einstein College of Medicine; N. Sarita Shah, Centers for Disease Control and Prevention; Yuming Ning, Albert Einstein College of Medicine; Salim Allana, Emory University; Angela Campbell, Emory University; Qin Hui, Emory University; Koleka Mlisana, University of KwaZulu-Natal; Pravi Moodley, University of KwaZulu-Natal; Neel Gandhi, Emory University
• Language: English
• Date: 2017-07-10
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
• License: Creative Commons Creative Commons CC0 1.0 Universal
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0180916
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 12
• Issue: 7
• Start Page: e0180916
• End Page: e0180916
• Grant/Funding Information: This study was funded by the US National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH www.nih.gov): R01AI087465 and R01AI089349 (both to NRG).; It was also supported in part by NIH/NIAID grants: K23AI083088 (to JCMB), K24AI114444 (to NRG), Emory Center for AIDS Research (CFAR www.cfar.emory.edu) P30AI050409, Einstein CFAR (www.einstein.yu.edu/centers/erc-center-for-aids-research) P30AI051519, Einstein/Montefiore Institute for Clinical and Translational Research (ICTR http://www.einstein.yu.edu/centers/ictr) UL1TR001073 and the Atlanta Clinical Translational Science Institute (ACTSI www.actsi.org) UL1TR000454.
• Keywords: RANDOMIZED CONTROLLED-TRIAL; Multidisciplinary Sciences; HIGH-DOSE VITAMIN-D-3; Science & Technology - Other Topics; Extensively drug-resistant tuberculosis; Tuberculosis; Science & Technology; Vitamin D; DOUBLE-BLIND; HIV; Sputum; Mycobacterium tuberculosis; Africans; Drug therapy; PULMONARY TUBERCULOSIS

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-hydroxyvi-tamin 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.