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PLoS One. 2016 Feb 12;11(2):e0148649. doi: 10.1371/journal.pone.0148649. eCollection 2016.

Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants.

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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.
Harvard School of Public Health, Boston, MA, United States of America.
Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
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.
Department of Pediatrics, University of KwaZulu-Natal, Durban, South Africa.
Children's Infectious Diseases Clinical Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.
University of Miami, Miami, FL, United States of America.
University of California San Diego, La Jolla, CA, United States of America, and Rady Children's Hospital, San Diego, CA, United States of America.



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.


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.


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.


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.


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