title: Genotype-independent association between profound vitamin D deficiency and delayed sputum smear conversion in pulmonary tuberculosis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of the Punjab, Quaid-e-Azam Campus, PO Box No 54590, Lahore, 54000, Pakistan. kashaf_junaid@hotmail.com.|Centre for Primary Care and Public Health, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AB, UK. kashaf_junaid@hotmail.com.
authors.forename: Kashaf
authors.initials: K
authors.lastname: Junaid
authors.affiliation: Department of Microbiology and Molecular Genetics, University of the Punjab, Quaid-e-Azam Campus, PO Box No 54590, Lahore, 54000, Pakistan. rehman_mmg@yahoo.com.
authors.forename: Abdul
authors.initials: A
authors.lastname: Rehman
authors.affiliation: Gulab Devi Chest Hospital, Lahore, 54000, Pakistan. doctortahir@hormail.com.
authors.forename: Tahir
authors.initials: T
authors.lastname: Saeed
authors.affiliation: Centre for Primary Care and Public Health, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AB, UK. d.a.jolliffe@qmul.ac.uk.
authors.forename: David A
authors.initials: DA
authors.lastname: Jolliffe
authors.affiliation: Genome Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK. kristie.wood@qmul.ac.uk.
authors.forename: Kristie
authors.initials: K
authors.lastname: Wood
authors.affiliation: Centre for Primary Care and Public Health, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AB, UK. a.martineau@qmul.ac.uk.
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Martineau
mesh_terms: D000293:Adolescent; D000328:Adult; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000235:genetics*; D013183:Sputum / Q000382:microbiology*; D014157:Transcription Factors / Q000235:genetics; D014397:Tuberculosis, Pulmonary / Q000473:pathology*; D014807:Vitamin D / Q000097:blood; D014808:Vitamin D Deficiency / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: C063898:DBP protein, human; D004268:DNA-Binding Proteins; D018167:Receptors, Calcitriol; D014157:Transcription Factors; D014807:Vitamin D; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase