title: Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants.
abstract: BACKGROUND
  This study examined the associations of 25-hydroxyvitamin D and specific host genetic variants that affect vitamin D levels or its effects on immune function, with the risk of TB or mortality in children.
  
  
  METHODS
  A case-cohort sample of 466 South African infants enrolled in P1041 trial (NCT00080119) underwent 25-hydroxyvitamin D testing by chemiluminescent immunoassay. Single nucleotide polymorphisms (SNPs) that alter the effect of vitamin D [e.g. vitamin D receptor (VDR)], vitamin D levels [e.g. vitamin D binding protein (VDBP)], or toll like receptor (TLR) expression (SIGIRR including adjacent genes PKP3 and TMEM16J) were identified by real-time PCR. Outcomes were time to TB, and to the composite of TB or death by 192 weeks of follow-up. Effect modification between vitamin D status and SNPs for outcomes was assessed.
  
  
  RESULTS
  Median age at 25-hydroxyvitamin D determination was 8 months; 11% were breastfed, 51% were HIV-infected and 26% had low 25-hydroxyvitamin D (<32ng/mL). By 192 weeks, 138 incident TB cases (43 definite/probable, and 95 possible) and 26 deaths occurred. Adjusting for HIV status and potential confounders, low 25-hydroxyvitamin D was associated with any TB (adjusted hazard ratio [aHR] 1.76, 95% CI 1.01-3.05; p = 0.046) and any TB or death (aHR 1.76, 95% CI 1.03-3.00; p = 0.038). Children with low 25-hydroxyvitamin D and TMEM 16J rs7111432-AA or PKP3 rs10902158-GG were at increased risk for probable/definite TB or death (aHR 8.12 and 4.83, p<0.05) and any TB or death (aHR 4.78 and 3.26, p<0.005) respectively; SNPs in VDBP, VDR, and vitamin D precursor or hydroxylation genes were not. There was significant interaction between low 25-hydroxyvitamin D and, TMEM 16J rs7111432-AA (p = 0.04) and PKP3 rs10902158-GG (p = 0.02) SNPs.
  
  
  CONCLUSIONS
  Two novel SNPs, thought to be associated with innate immunity, in combination with low vitamin D levels were identified as increasing a young child's risk of developing TB disease or death. Identifying high-risk children and providing targeted interventions such as vitamin D supplementation may be beneficial.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00080119.
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.|Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.
authors.forename: Amita
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Harvard School of Public Health, Boston, MA, United States of America.
authors.forename: Grace
authors.initials: G
authors.lastname: Montepiedra
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.|Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.
authors.forename: Akshay
authors.initials: A
authors.lastname: Gupte
authors.affiliation: Harvard School of Public Health, Boston, MA, United States of America.
authors.forename: Bret
authors.initials: B
authors.lastname: Zeldow
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jubulis
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Barbara
authors.initials: B
authors.lastname: Detrick
authors.affiliation: Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Avy
authors.initials: A
authors.lastname: Violari
authors.affiliation: Medical Research Council: Respiratory and Meningeal Pathogens Research Unit and Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Shabir
authors.initials: S
authors.lastname: Madhi
authors.affiliation: Department of Pediatrics, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Raziya
authors.initials: R
authors.lastname: Bobat
authors.affiliation: Children's Infectious Diseases Clinical Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Mark
authors.initials: M
authors.lastname: Cotton
authors.affiliation: University of Miami, Miami, FL, United States of America.
authors.forename: Charles
authors.initials: C
authors.lastname: Mitchell
authors.affiliation: University of California San Diego, La Jolla, CA, United States of America, and Rady Children's Hospital, San Diego, CA, United States of America.
authors.forename: Stephen
authors.initials: S
authors.lastname: Spector
mesh_terms: D000328:Adult; D000075368:Anoctamins; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D049294:Phospholipid Transfer Proteins; D051191:Plakophilins / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000276:immunology; D014808:Vitamin D Deficiency / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D014809:Vitamin D-Binding Protein / Q000235:genetics / Q000276:immunology
chemical_list: C570645:ANO9 protein, human; D000075368:Anoctamins; D008565:Membrane Proteins; C495339:PKP3 protein, human; D049294:Phospholipid Transfer Proteins; D051191:Plakophilins; D018167:Receptors, Calcitriol; D017472:Receptors, Interleukin-1; C546891:SIGIRR protein, human; C579457:VDR protein, human; D014809:Vitamin D-Binding Protein; D014807:Vitamin D; C104450:25-hydroxyvitamin D