Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants.
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) underwen...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4752266?pdf=render |
| _version_ | 1818565464776769536 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Amita Gupta |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T01:41:42Z |
| format | Article |
| id | doaj.art-7c264a3b2f73418bb0a482e330e52d88 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T01:41:42Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-7c264a3b2f73418bb0a482e330e52d882022-12-21T23:21:43ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01112e014864910.1371/journal.pone.0148649Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants.Amita GuptaGrace MontepiedraAkshay GupteBret ZeldowJennifer JubulisBarbara DetrickAvy ViolariShabir MadhiRaziya BobatMark CottonCharles MitchellStephen SpectorIMPAACT NWCS113 and P1041 Study TeamThis 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.http://europepmc.org/articles/PMC4752266?pdf=render |
| spellingShingle | 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 Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants. PLoS ONE |
| title | Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants. |
| title_full | Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants. |
| title_fullStr | Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants. |
| title_full_unstemmed | Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants. |
| title_short | Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants. |
| title_sort | low vitamin d levels combined with pkp3 sigirr tmem16j host variants is associated with tuberculosis and death in hiv infected and exposed infants |
| url | http://europepmc.org/articles/PMC4752266?pdf=render |
| work_keys_str_mv | AT amitagupta lowvitamindlevelscombinedwithpkp3sigirrtmem16jhostvariantsisassociatedwithtuberculosisanddeathinhivinfectedandexposedinfants AT gracemontepiedra lowvitamindlevelscombinedwithpkp3sigirrtmem16jhostvariantsisassociatedwithtuberculosisanddeathinhivinfectedandexposedinfants AT akshaygupte lowvitamindlevelscombinedwithpkp3sigirrtmem16jhostvariantsisassociatedwithtuberculosisanddeathinhivinfectedandexposedinfants AT bretzeldow lowvitamindlevelscombinedwithpkp3sigirrtmem16jhostvariantsisassociatedwithtuberculosisanddeathinhivinfectedandexposedinfants AT jenniferjubulis lowvitamindlevelscombinedwithpkp3sigirrtmem16jhostvariantsisassociatedwithtuberculosisanddeathinhivinfectedandexposedinfants AT barbaradetrick lowvitamindlevelscombinedwithpkp3sigirrtmem16jhostvariantsisassociatedwithtuberculosisanddeathinhivinfectedandexposedinfants AT avyviolari lowvitamindlevelscombinedwithpkp3sigirrtmem16jhostvariantsisassociatedwithtuberculosisanddeathinhivinfectedandexposedinfants AT shabirmadhi lowvitamindlevelscombinedwithpkp3sigirrtmem16jhostvariantsisassociatedwithtuberculosisanddeathinhivinfectedandexposedinfants AT raziyabobat lowvitamindlevelscombinedwithpkp3sigirrtmem16jhostvariantsisassociatedwithtuberculosisanddeathinhivinfectedandexposedinfants AT markcotton lowvitamindlevelscombinedwithpkp3sigirrtmem16jhostvariantsisassociatedwithtuberculosisanddeathinhivinfectedandexposedinfants AT charlesmitchell lowvitamindlevelscombinedwithpkp3sigirrtmem16jhostvariantsisassociatedwithtuberculosisanddeathinhivinfectedandexposedinfants AT stephenspector lowvitamindlevelscombinedwithpkp3sigirrtmem16jhostvariantsisassociatedwithtuberculosisanddeathinhivinfectedandexposedinfants AT impaactnwcs113andp1041studyteam lowvitamindlevelscombinedwithpkp3sigirrtmem16jhostvariantsisassociatedwithtuberculosisanddeathinhivinfectedandexposedinfants |