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

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 disea...

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Veröffentlicht in:	PloS one Jg. 12; H. 7; S. e0180916
Hauptverfasser:	Magee, Matthew J., Sun, Yan V., Brust, James C. M., Shah, N. Sarita, Ning, Yuming, Allana, Salim, Campbell, Angela, Hui, Qin, Mlisana, Koleka, Moodley, Pravi, Gandhi, Neel R.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Public Library of Science 01.07.2017 Public Library of Science (PLoS)
Schlagworte:	25-Hydroxyvitamin D Adult Age Antiinfectives and antibacterials Biology and Life Sciences Confidence intervals Conversion Culture Deoxyribonucleic acid DNA Drug resistance Female Genomic analysis Genomics Health risks HIV HIV Infections - genetics Human immunodeficiency virus Humans Immune response Immune system Impact resistance Inflammation Male Medicine and Health Sciences Multidrug resistance Multidrug resistant organisms Patients People and Places Physical sciences Polymorphism, Single Nucleotide - genetics Populations Proportional Hazards Models Prospective Studies Receptors, Calcitriol - genetics Risk Single-nucleotide polymorphism Smear Smoking South Africa Sputum Sputum - microbiology Tuberculosis Tuberculosis, Multidrug-Resistant - genetics Vitamin D Vitamin D - analogs & derivatives Vitamin D - metabolism Vitamin D receptors Atlanta Georgia United States > US South Africa
ISSN:	1932-6203, 1932-6203
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Abstract	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. 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. 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). 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.
AbstractList	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.BACKGROUNDVitamin 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.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.METHODSWe 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.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).RESULTSGenomic 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).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.CONCLUSIONSPolymorphisms 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. 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. 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.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.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).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. 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. 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. 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). 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. 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.
Author	Sun, Yan V. Hui, Qin Moodley, Pravi Shah, N. Sarita Campbell, Angela Magee, Matthew J. Mlisana, Koleka Allana, Salim Ning, Yuming Brust, James C. M. Gandhi, Neel R.
AuthorAffiliation	4 US Centers for Disease Control and Prevention, Atlanta, United States of America 1 Division of Epidemiology and Biostatistics, School of Public Health, Georgia State University, Atlanta, United States of America 2 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, United States of America 3 Divisions of General Internal Medicine and Infectious Diseases, Albert Einstein College of Medicine, Bronx, United States of America 5 School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa 6 Division of Infectious Diseases, Emory School of Medicine, Emory University, Atlanta, United States of America 7 Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, United States of America Central University of Tamil Nadu, INDIA
AuthorAffiliation_xml	– name: 6 Division of Infectious Diseases, Emory School of Medicine, Emory University, Atlanta, United States of America – name: 2 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, United States of America – name: 1 Division of Epidemiology and Biostatistics, School of Public Health, Georgia State University, Atlanta, United States of America – name: 4 US Centers for Disease Control and Prevention, Atlanta, United States of America – name: Central University of Tamil Nadu, INDIA – name: 7 Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, United States of America – name: 3 Divisions of General Internal Medicine and Infectious Diseases, Albert Einstein College of Medicine, Bronx, United States of America – name: 5 School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
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CitedBy_id	crossref_primary_10_1016_j_ijtb_2022_05_011 crossref_primary_10_1016_j_meegid_2022_105324 crossref_primary_10_1371_journal_pgen_1010387 crossref_primary_10_1007_s00403_022_02399_z crossref_primary_10_1080_16070658_2020_1757878 crossref_primary_10_1136_bmjopen_2020_039935 crossref_primary_10_1016_j_genrep_2018_08_001 crossref_primary_10_1016_j_meegid_2020_104204 crossref_primary_10_1097_MD_0000000000011732 crossref_primary_10_1016_j_rmcr_2018_09_005 crossref_primary_10_1371_journal_pone_0267917 crossref_primary_10_1080_14787210_2022_2081546
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Publisher	Public Library of Science Public Library of Science (PLoS)
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A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis' publication-title: BMC infectious diseases doi: 10.1186/1471-2334-13-22 – volume: 449 start-page: 851 issue: 7164 year: 2007 ident: ref22 article-title: A second generation human haplotype map of over 3.1 million SNPs publication-title: Nature doi: 10.1038/nature06258 – volume: 87 start-page: 295 issue: 4 year: 2007 ident: ref17 article-title: Vitamin D receptor gene polymorphisms and sputum conversion time in pulmonary tuberculosis patients publication-title: Tuberculosis doi: 10.1016/j.tube.2007.03.001 – volume: 368 start-page: 1575 issue: 9547 year: 2006 ident: ref4 article-title: Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa publication-title: Lancet doi: 10.1016/S0140-6736(06)69573-1 – volume: 16 start-page: 1522 issue: 11 year: 2012 ident: ref16 article-title: Risk and outcome of multidrug-resistant tuberculosis: vitamin D receptor polymorphisms and serum 25(OH)D publication-title: The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease doi: 10.5588/ijtld.12.0122 – volume: 15 start-page: 528 issue: 5 year: 2015 ident: ref12 article-title: Adjunctive vitamin D for treatment of active tuberculosis in India: a randomised, double-blind, placebo-controlled trial publication-title: The Lancet Infectious diseases doi: 10.1016/S1473-3099(15)70053-8 – volume: 2014 start-page: 903680 year: 2014 ident: ref9 article-title: Anti-Inflammatory and Antimicrobial Actions of Vitamin D in Combating TB/HIV publication-title: Scientifica doi: 10.1155/2014/903680 – volume: 375 start-page: 1830 issue: 9728 year: 2010 ident: ref3 article-title: Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis publication-title: Lancet doi: 10.1016/S0140-6736(10)60410-2 – ident: ref6 – volume: 6 start-page: e15841 issue: 1 year: 2011 ident: ref20 article-title: Culture conversion among HIV co-infected multidrug-resistant tuberculosis patients in Tugela Ferry, South Africa publication-title: PloS one doi: 10.1371/journal.pone.0015841 – volume: 190 start-page: 920 issue: 5 year: 2004 ident: ref15 article-title: Association between vitamin D receptor gene polymorphisms and response to treatment of pulmonary tuberculosis publication-title: The Journal of infectious diseases doi: 10.1086/423212 – ident: ref21 – year: 2016 ident: ref1 article-title: WHO. 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Snippet	Vitamin D modulates the inflammatory and immune response to tuberculosis (TB) and also mediates the induction of the antimicrobial peptide cathelicidin.... Background Vitamin D modulates the inflammatory and immune response to tuberculosis (TB) and also mediates the induction of the antimicrobial peptide... Background Vitamin D modulates the inflammatory and immune response to tuberculosis (TB) and also mediates the induction of the antimicrobial peptide...
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SubjectTerms	25-Hydroxyvitamin D Adult Age Antiinfectives and antibacterials Biology and Life Sciences Confidence intervals Conversion Culture Deoxyribonucleic acid DNA Drug resistance Female Genomic analysis Genomics Health risks HIV HIV Infections - genetics Human immunodeficiency virus Humans Immune response Immune system Impact resistance Inflammation Male Medicine and Health Sciences Multidrug resistance Multidrug resistant organisms Patients People and Places Physical sciences Polymorphism, Single Nucleotide - genetics Populations Proportional Hazards Models Prospective Studies Receptors, Calcitriol - genetics Risk Single-nucleotide polymorphism Smear Smoking South Africa Sputum Sputum - microbiology Tuberculosis Tuberculosis, Multidrug-Resistant - genetics Vitamin D Vitamin D - analogs & derivatives Vitamin D - metabolism Vitamin D receptors
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Title	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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