Enhancer polymorphism rs10865710 associated with traumatic sepsis is a regulator of PPARG gene expression
Enhancer polymorphism rs10865710 associated with traumatic sepsis is a regulator of PPARG gene expression
复制标题
与创伤性脓毒症相关的增强子多态性 rs10865710 是 PPARG 基因表达的调节因子
DOI：
10.1186/s13054-019-2707-z
复制
发表时间：
2019-12-30
期刊：
影响因子：
15.1
通讯作者：
Zhang, Anqiang
中科院分区：
文献类型：
--
作者：
Lu, Hongxiang;Wen, Dalin;Zhang, Anqiang
背景：过氧化物酶体增殖物激活受体γ（PPAR）。是脓毒症的主要调节因子我们先前的研究确定了增强子多态性rs10865710C/G与创伤患者脓毒症的易感性相关。我们进行了两个阶段的队列研究，整合潜在的功能变异，修改创伤septics.Methods的易感性的生物学实验：改进的多重连接检测反应（iMLDR）基因型rs10865710在797例汉族创伤患者在重庆。在贵州334例患者中验证了临床相关性。通过双荧光素酶报告基因分析和电泳迁移率变动分析（EMSA）探讨rs10865710在转录调控中的潜在功能。PPAR的表达。通过表达数量性状基因座（e-QTL）和western blot分析，对2000年的水稻产量进行了评估。相关性结果证实rs10865710与重庆和贵州队列创伤患者的脓毒症风险显著强相关等位基因剂量效应的OR值分别为1.41（1.11-1.79），P = 0.004和1.45（1.01-2.09），P = 0.046。一项对两个队列的荟萃分析和一项先前的研究表明了这种关联的强有力证据优势模式OR = 1.41（1.17-1.71），P = 0.0004，优势模式OR = 1.78（1.34-2.36），P <0.0001;（1.20-1.58），P <0.0001）。功能实验证实rs10865710是影响增强子活性（G vs. C，0.068 +/-0.004 vs. 0.096 +/-0.002，P = 0.0005）和CREB 2结合的致病变体。表达分析还表明，vd rs10865710基因型与PPAR γ表达水平相关。（显性效应P = 9.2 x 10（-5），隐性效应P = 0.005）。我们的研究提供了证据，增强子区多态性rs10865710可能影响转录因子结合和调节PPAR γ表达，从而赋予创伤性脓毒症的易感性。
Background: Peroxisome proliferator-activated receptor gamma (PPAR.) is a major regulator in sepsis. Our previous study identified the enhancer polymorphism rs10865710C/G to be associated with susceptibility to sepsis in trauma patients. We performed two-stage cohort studies integrating biological experiments of potential functional variants that modify susceptibility to traumatic sepsis.Methods: Improved multiplex ligation detection reaction (iMLDR) was used to genotype rs10865710 in 797 Han Chinese trauma patients in Chongqing. Clinical relevance was validated in 334 patients in Guizhou. The potential function of rs10865710 in transcriptional regulation was explored through a dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). Expression of PPAR. was assessed by expression quantitative trait locus (e-QTL) and western blot analyses.Results: The association results confirmed rs10865710 to be significantly strongly associated with sepsis risk in trauma patients of the Chongqing and Guizhou cohorts (OR = 1.41 (1.11-1.79), P = 0.004 and OR = 1.45 (1.01-2.09), P = 0.046, both for allele-dose effect, respectively). A meta-analysis of both cohorts and a previous study indicated strong evidence for this association (OR = 1.41 (1.17-1.71), P = 0.0004 for the dominant model, OR = 1.78 (1.34-2.36), P < 0.0001 for the recessive model and OR = 1.38 (1.20-1.58), P < 0.0001 for the allelic model). Functional experiments verified that rs10865710 was a causative variant influencing enhancer activity (G vs. C, 0.068 +/- 0.004 vs. 0.096 +/- 0.002, P = 0.0005) and CREB2 binding. Expression analysis also indicatevd rs10865710 genotypes to be associated with levels of PPAR gamma expression (P = 9.2 x 10(-5) for dominant effect and P = 0.005 for recessive effect).Conclusions: Our study provides evidence that the enhancer-region polymorphism rs10865710 might influence transcription factor binding and regulate PPAR gamma expression, thus conferring susceptibility to traumatic sepsis.