Impaired resolution of blood transcriptomes through tuberculosis treatment with diabetes comorbidity.
Impaired resolution of blood transcriptomes through tuberculosis treatment with diabetes comorbidity.
复制标题
DOI：
10.1002/ctm2.1375
复制
发表时间：
2023-09
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
与没有糖尿病的人相比，糖尿病患者更有可能患上结核病，而且结核病治疗结果不佳。我们之前的研究表明，肺结核-糖尿病(TB-DM)共病患者的血液转录本在确诊时有过度炎症和干扰素反应减少。目前尚不清楚这种情况是否会持续到治疗过程中，并导致不良后果。在南非、印度尼西亚和罗马尼亚招募的肺结核患者根据确诊时和治疗6个月后的糖化血红蛋白浓度，被归类为患有结核病-糖尿病、糖尿病前期的结核病、与结核病相关的高血糖或仅患有结核病。通过无偏向RNA-Seq和靶向多重连接依赖的探针扩增检测诊断和整个治疗期间血液中的基因表达。转录本数据通过纵向混合模型回归分析，以确定临床组之间的基因表达是否随着时间的推移而存在差异。建立了跨组结核病治疗反应的预测模型，并进行了交叉测试。结核病和结核病-糖尿病患者的基因表达在诊断时是不同的，并且在所有临床组中都受到结核病治疗的调节，但程度不同，因此在整个过程中，结核病-糖尿病患者与单纯结核病患者之间的差异仍然存在。在结核病治疗期间，一些基因的表达增加，而另一些基因的表达减少：一些基因在结核病-糖尿病患者中持续高表达，而另一些基因在仅患有结核病的患者中持续高表达。在整个治疗过程中，与先天免疫反应、抗微生物免疫和炎症相关的基因在TB-DM患者中显著上调。无论糖尿病状态如何，临床组的总体变化模式都是相似的，这使得预测结核病治疗的模型得以开发。在结核病治疗期间，结核病-糖尿病患者加剧的转录组变化需要更长的时间才能解决，这意味着在治疗完成后，它们仍不同于未合并并发症的结核病患者。这可能表明TB-DM的炎症反应持续时间延长，需要长期治疗或宿主导向治疗才能完全治愈。基于转录组的结核病治疗反应生物标记物签名的开发应包括糖尿病患者，以供跨人群使用。肺结核患者的异常血液转录本在同时患有2型糖尿病的患者中会进一步改变。在肺结核合并糖尿病患者的整个结核病治疗过程中，过度的炎症反应持续存在。将患有糖尿病或高血糖升高的结核病患者包括在内，可以开发出生物签名，准确预测正常血糖/糖尿病谱和跨地域人群的结核病治疗反应。
People with diabetes are more likely to develop tuberculosis (TB) and to have poor TB‐treatment outcomes than those without. We previously showed that blood transcriptomes in people with TB‐diabetes (TB‐DM) co‐morbidity have excessive inflammatory and reduced interferon responses at diagnosis. It is unknown whether this persists through treatment and contributes to the adverse outcomes. Pulmonary TB patients recruited in South Africa, Indonesia and Romania were classified as having TB‐DM, TB with prediabetes, TB‐related hyperglycaemia or TB‐only, based on glycated haemoglobin concentration at TB diagnosis and after 6 months of TB treatment. Gene expression in blood at diagnosis and intervals throughout treatment was measured by unbiased RNA‐Seq and targeted Multiplex Ligation‐dependent Probe Amplification. Transcriptomic data were analysed by longitudinal mixed‐model regression to identify whether genes were differentially expressed between clinical groups through time. Predictive models of TB‐treatment response across groups were developed and cross‐tested. Gene expression differed between TB and TB‐DM patients at diagnosis and was modulated by TB treatment in all clinical groups but to different extents, such that differences remained in TB‐DM relative to TB‐only throughout. Expression of some genes increased through TB treatment, whereas others decreased: some were persistently more highly expressed in TB‐DM and others in TB‐only patients. Genes involved in innate immune responses, anti‐microbial immunity and inflammation were significantly upregulated in people with TB‐DM throughout treatment. The overall pattern of change was similar across clinical groups irrespective of diabetes status, permitting models predictive of TB treatment to be developed. Exacerbated transcriptome changes in TB‐DM take longer to resolve during TB treatment, meaning they remain different from those in uncomplicated TB after treatment completion. This may indicate a prolonged inflammatory response in TB‐DM, requiring prolonged treatment or host‐directed therapy for complete cure. Development of transcriptome‐based biomarker signatures of TB‐treatment response should include people with diabetes for use across populations. Aberrant blood transcriptomes in people with tuberculosis are further altered in people who also have type 2 diabetes. Excessive inflammatory responses persist throughout tuberculosis treatment in tuberculosis‐diabetes co‐morbid patients. Inclusion of TB patients with diabetes or elevated hyperglycaemia permits the development of biosignatures which accurately predict tuberculosis‐treatment response across the normoglycaemia/diabetes spectrum and across geographical populations.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
9.1
作者：
Geluk, Annemieke;van Meijgaarden, Krista E.;Ottenhoff, Tom H. M.
通讯作者：
Ottenhoff, Tom H. M.
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
3.7
作者：
Kumar NP;Banurekha VV;Nair D;Sridhar R;Kornfeld H;Nutman TB;Babu S
通讯作者：
Babu S