Dataset Information

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

ABSTRACT: 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.ClinicalTrials.gov NCT00080119.

SUBMITTER: Gupta A

PROVIDER: S-EPMC4752266 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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

Gupta Amita A Montepiedra Grace G Gupte Akshay A Zeldow Bret B Jubulis Jennifer J Detrick Barbara B Violari Avy A Madhi Shabir S Bobat Raziya R Cotton Mark M Mitchell Charles C Spector Stephen S

PloS one 20160212 2

<h4>Background</h4>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.<h4>Methods</h4>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 (VD ...[more]

PMID: 26872154

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Project description:BACKGROUND:Poor vitamin D status is a global health problem and common in patients with human immunodeficiency virus (HIV) in high-income countries. There is less evidence on prevalence of vitamin D deficiency and nutrition and growth in HIV-infected and -exposed children in low- and middle-income countries. OBJECTIVES:To determine the vitamin D status in Batswana HIV-infected mothers and their children, differences among HIV-infected mothers and between HIV-exposed and -infected infants and children, and associations between vitamin D and disease-related outcomes, nutrition, and growth. METHODS:This was a cross-sectional study of HIV+ mothers and HIV-exposed infants and unrelated children (1-7.9 years). Serum 25-hydroxyvitamin D (25(OH)D) was measured, among other nutritional indicators, for mothers, infants and children. Vitamin D status for HIV-infected mothers and children, and an immune panel was assessed. History of HIV anti-retroviral medications and breastfeeding were obtained. Data were collected prior to universal combination antiretroviral therapy in pregnancy. RESULTS:Mothers (n = 36) had a mean serum 25(OH)D of 37.2±12.4ng/mL; 11% had insufficient (<20ng/mL), 17% moderately low (20.0-29.9ng/mL) and 72% sufficient (≥30ng/mL) concentrations. No infants (n = 36) or children (n = 48) were vitamin D insufficient; 22% of HIV- and no HIV+ infants had moderately low concentrations and 78% of HIV- and 100% of HIV+ infants had sufficient status, 8% of HIV- and no HIV+ children had moderately low concentrations and 92% of HIV- and 100% HIV+ children had sufficient concentrations. HIV+ children had significantly lower length/height Z scores compared to HIV- children. Length/height Z score was positively correlated with serum 25(OH)D in all children (r = 0.33, p = 0.023), with a stronger correlation in the HIV+ children (r = 0.47 p = 0.021). In mothers, serum 25(OH)D was positively associated with CD4% (r = 0.40, p = 0.016). CONCLUSIONS:Results showed a low prevalence of vitamin D insufficiency in Botswana. Growth was positively correlated with vitamin D status in HIV-exposed children, and HIV+ children had poorer linear growth than HIV- children.

Project description:BackgroundVitamin D is a potent immunomodulator, but its impact on morbidity and mortality among infants remains unclear.ObjectiveThe objective of the study was to prospectively assess the association of vitamin D status with mortality, morbidity, and growth during the first 2 y of life.MethodsA prospective cohort of 253 HIV-infected and 948 HIV-exposed Tanzanian infants enrolled in a randomized trial of multivitamins (not including vitamin D) was studied. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured at 5-7 wk of age and infants were followed at monthly clinic visits until 24 mo. Physicians performed a clinical exam every 3 mo or when an illness was noted.ResultsSerum 25(OH)D concentrations were (means ± SDs) 18.6 ± 10.3 ng/mL and 18.1 ± 9.2 ng/mL for HIV-infected and HIV-exposed infants, respectively. Unexpectedly, serum 25(OH)D concentrations ≥30 ng/mL were significantly associated with higher mortality as compared to the 20-29.9 ng/mL reference for HIV-infected (HR: 2.47; 95% CI: 1.13, 5.44; P = 0.02) and HIV-exposed (HR: 4.00; 95% CI: 1.67, 9.58; P < 0.01) infants after multivariate adjustment. We found no statistically significant association between 25(OH)D concentrations <10 ng/mL and mortality for HIV-infected (HR: 1.43; 95% CI: 0.74, 2.78; P = 0.29) and HIV-exposed (HR: 1.56; 95% CI: 0.60, 4.03; P = 0.36) infants. Among HIV-exposed infants, 25(OH)D concentrations ≥30 ng/mL were significantly associated with clinical [incidence ratio rate (IRR): 1.34; 95% CI: 1.06,1.70; P = 0.02] and confirmed (IRR: 1.71; 95% CI: 1.71; 1.15, 2.54; P < 0.01) malaria diagnoses, whereas concentrations of <10 ng/mL were associated with oral candidiasis (IRR: 1.47; 95% CI: 1.00-2.15; P = 0.046) and wasting (HR: 1.71; 95% CI: 1.20, 2.43; P < 0.01).ConclusionThe observational design of this study does not allow for causal interpretation; however, the results indicate a strong need for additional studies of vitamin D among HIV-infected and -exposed children, particularly in malaria-endemic settings. The parent trial was registered at clinicaltrials.gov as NCT00197730.

Dataset Information

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

Publications

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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