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

BackgroundThis 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.MethodsA 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.FindingsMedian age at 25-hydroxyvitamin D determination was 8 months; 11% were breastfed, 51% were HIV-infected and 26% had low 25-hydroxyvitamin D (TMEM 16J rs7111432-AA or PKP3 rs10902158-GG were at increased risk for probable/definite TB or death (aHR 8.12 and 4.83, pTMEM 16J rs7111432-AA (p = 0.04) and PKP3 rs10902158-GG (p = 0.02) SNPs.ConclusionsTwo 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 RegistrationClinicalTrials.gov NCT00080119背景 本研究探讨了25-羟维生素D（25-hydroxyvitamin D）以及影响维生素D水平或其对免疫功能作用的特定宿主遗传变异，与儿童结核病（Tuberculosis, TB）发病风险或死亡风险的关联。 方法 本研究纳入参与P1041试验（临床试验编号：NCT00080119）的466名南非婴儿组成的病例队列样本，采用化学发光免疫分析法检测其血清25-羟维生素D水平。通过实时荧光定量PCR（real-time PCR）鉴定可影响维生素D作用（如维生素D受体（VDR））、维生素D水平（如维生素D结合蛋白（VDBP））或Toll样受体（TLR）表达（SIGIRR及其相邻基因PKP3与TMEM16J）的单核苷酸多态性（Single Nucleotide Polymorphisms, SNPs）。本研究的结局指标为随访至192周时的结核病发生时间，以及结核病或死亡的复合结局发生时间，并评估了维生素D营养状态与单核苷酸多态性之间对结局的交互作用。 结果 25-羟维生素D检测时的中位年龄为8个月；研究对象中11%为母乳喂养儿，51%为人类免疫缺陷病毒（HIV）感染者，26%存在低25-羟维生素D血症。TMEM16J rs7111432-AA基因型与PKP3 rs10902158-GG基因型携带者发生很可能/确诊结核病或死亡的风险升高，校正后风险比（adjusted hazard ratio, aHR）分别为8.12与4.83，对应的统计学显著性p值分别为0.04与0.02。 结论 本研究鉴定出两个与固有免疫相关的新型单核苷酸多态性，其与低维生素D水平联合可升高幼儿罹患结核病或死亡的风险。识别高危儿童并给予维生素D补充等针对性干预措施或可带来临床获益。 试验注册 临床试验注册平台（ClinicalTrials.gov）编号：NCT00080119