Suchy-Dicey Astrid, Heckbert Susan R, Smith Nicholas L, McKnight Barbara, Rotter Jerome I, Chen Yd Ida, Psaty Bruce M, Enquobahrie Daniel A
Department of Epidemiology, University of Washington Seattle, WA, USA.
Department of Epidemiology, University of Washington Seattle, WA, USA ; Department of Pharmacy, University of Washington Seattle, WA, USA ; Group Health Research Institute, Group Health Cooperative Seattle, WA, USA.
Int J Mol Epidemiol Genet. 2014 Feb 17;5(1):22-30. eCollection 2014.
Thiazide diuretics and statins are used to improve cardiovascular outcomes, but may also cause type 2 diabetes (T2DM), although mechanisms are unknown. Gene expression studies may facilitate understanding of these associations. Participants from ongoing population-based studies were sampled for these longitudinal studies of peripheral blood microarray gene expression, and followed to incident diabetes. All sampled subjects were statin or thiazide users. Those who developed diabetes during follow-up comprised cases (44 thiazide users; 19 statin users), and were matched to drug-using controls who did not develop diabetes on several factors. Supervised normalization, surrogate variable analyses removed technical bias and confounding. Differentially-expressed genes were those with a false discovery rate Q-value<0.05. Among thiazide users, diabetes cases had significantly different expression of CCL14 (down-regulated 6%, Q-value=0.0257), compared with controls. Among statin users, diabetes cases had marginal but insignificantly different expression of ZNF532 (up-regulated 15%, Q-value=0.0584), CXORF21 (up-regulated 11%, Q-value=0.0584), and ZNHIT3 (up-regulated 19%, Q-value=0.0959), compared with controls. These genes comprise potential targets for future expression or mechanistic research on medication-related diabetes development.
噻嗪类利尿剂和他汀类药物用于改善心血管疾病预后，但也可能导致2型糖尿病（T2DM），尽管其机制尚不清楚。基因表达研究可能有助于理解这些关联。从正在进行的基于人群的研究中选取参与者，对其外周血微阵列基因表达进行这些纵向研究，并随访至发生糖尿病。所有采样对象均为他汀类药物或噻嗪类药物使用者。随访期间发生糖尿病的患者为病例组（44名噻嗪类药物使用者；19名他汀类药物使用者），并在多个因素上与未发生糖尿病的用药对照组进行匹配。通过监督归一化、替代变量分析消除技术偏差和混杂因素。差异表达基因是错误发现率Q值<0.05的基因。在噻嗪类药物使用者中，与对照组相比，糖尿病病例的CCL14表达有显著差异（下调6%，Q值=0.0257）。在他汀类药物使用者中，与对照组相比，糖尿病病例的ZNF532（上调15%，Q值=0.0584）、CXORF21（上调11%，Q值=0.0584）和ZNHIT3（上调19%，Q值=0.0959）表达有边缘性差异但不显著。这些基因构成了未来关于药物相关糖尿病发生的表达或机制研究的潜在靶点。
