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

Amita Gupta, Grace Montepiedra, Akshay Gupte, Bret Zeldow, Jennifer Jubulis, Barbara Detrick, Avy Violari, Shabir Madhi, Raziya Bobat, Mark Cotton, Charles Mitchell, Stephen Spector, IMPAACT NWCS113 and P1041 Study Team, Amita Gupta, Grace Montepiedra, Akshay Gupte, Bret Zeldow, Jennifer Jubulis, Barbara Detrick, Avy Violari, Shabir Madhi, Raziya Bobat, Mark Cotton, Charles Mitchell, Stephen Spector, IMPAACT NWCS113 and P1041 Study Team

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.

Findings: 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.

Trial registration: ClinicalTrials.gov NCT00080119.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Consort diagram for case-cohort study.
Fig 1. Consort diagram for case-cohort study.
Fig 2. Cox Proportional Hazard Models for…
Fig 2. Cox Proportional Hazard Models for TB disease or death, looking at (A) low vitamin D (LVD) status as risk factor ignoring genetic variant, (B) TMEM16J rs7111432 variant as risk factor ignoring LVD status, and (C) PKP3 rs10902158 variant as risk factor ignoring LVD status.
Model 1 adjusts for HIV infection status. Model 2 adjusts for HIV status, season, site, sex, weight z-score, type of house, mother prev TB diagnosis, age (in months) at plasma draw date, and INH/Placebo group. Model 3 adjusts for HIV status, site, sex, weight z-score, type of house, mother prev TB diagnosis, and INH/Placebo group. Evts/LVD = no. of events/no. of subjects with low vitamin D (%). Evts/NotLVD = no. of events/no. of subjects without low vitamin D (%). Evts/AA = no. of events/no. of subjects with AA genotype (%). Evts/NotAA = no. of events/no. of subjects without AA genotype (%). Evts/GG = no. of events/no. of subjects with GG genotype (%). Evts/NotGG = no. of events/no. of subjects without GG genotype (%).
Fig 3. Kaplan-Meier Plots on Tuberculosis Free…
Fig 3. Kaplan-Meier Plots on Tuberculosis Free Survival (from all available data in case-cohort) by (A) Vitamin D status, (B) Vitamin D status / rs7111432 variant and (C) Vitamin D status / rs10902158 variant.
Risk differences were computed as the differences in Kaplan-Meier survival estimates at end of follow-up period for this analysis, and were not adjusted for covariates.
Fig 4. Cox Proportional Hazard Models for…
Fig 4. Cox Proportional Hazard Models for TB disease or death, looking at (A) combination of low Vitamin D (LVD) status and TMEM 16J rs7111432 variant [AA genotype or not] as risk factor, and (B) combination of LVD status and PKP3 rs10902158 variant [GG genotype or not] as risk factor.
A: Model adjusts for HIV status, season, site, sex, weight z-score, type of house, mother with previous TB diagnosis, age (in months) at plasma draw date, and INH/Placebo group. B: Model adjusts for HIV status, season, site, sex, weight z-score, type of house, mother with previous TB diagnosis, age (in months) at plasma draw date, and INH/Placebo group.

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