BackgroundPeroxisome proliferator-activated receptor gamma (PPARγ) 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.MethodsImproved 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 PPARγ was assessed by expression quantitative trait locus (e-QTL) and western blot analyses.ResultsThe 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 PPARγ expression (P = 9.2 × 10−5 for dominant effect and P = 0.005 for recessive effect).ConclusionsOur study provides evidence that the enhancer-region polymorphism rs10865710 might influence transcription factor binding and regulate PPARγ expression, thus conferring susceptibility to traumatic sepsis.Trial registrationClinicalTrials.gov, NCT01713205. Registered 18 October 2012, retrospectively registered.

中文翻译：

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与创伤性败血症相关的增强子多态性 rs10865710 是 PPARG 基因表达的调节因子

背景过氧化物酶体增殖物激活受体γ (PPARγ) 是败血症的主要调节剂。我们之前的研究确定了增强子多态性 rs10865710C/G 与创伤患者败血症的易感性相关。我们进行了两阶段队列研究，整合了改变创伤性败血症易感性的潜在功能变异的生物学实验。方法改进的多重连接检测反应 (iMLDR) 用于重庆 797 名汉族创伤患者的基因分型 rs10865710。在贵州 334 名患者中验证了临床相关性。rs10865710 在转录调控中的潜在功能通过双荧光素酶报告基因检测和电泳迁移率变化检测 (EMSA) 进行了探索。通过表达数量性状基因座（e-QTL）和蛋白质印迹分析评估 PPARγ 的表达。 结果 关联结果证实 rs10865710 与重庆和贵州队列创伤患者的败血症风险显着强相关（OR = 1.41（1.11-1.79） )，P = 0.004 和 OR = 1.45 (1.01–2.09)，P = 0.046，分别针对等位基因剂量效应）。对两个队列和先前研究的荟萃分析表明这种关联的有力证据（OR = 1.41（1.17-1.71），显性模型 P = 0.0004，OR = 1.78（1.34-2.36），隐性模型 P < 0.0001模型和 OR = 1.38 (1.20–1.58)，等位基因模型 P < 0.0001）。功能实验证实 rs10865710 是影响增强子活性（G 对 C，0.068 ± 0.004 对 0.096 ± 0.002，P = 0.0005）和 CREB2 结合的致病变异。表达分析还表明 vd rs10865710 基因型与 PPARγ 表达水平相关（显性效应 P = 9.2 × 10-5，隐性效应 P = 0.005）。结论我们的研究提供了证据表明增强子区域多态性 rs10865710 可能影响转录因子结合并调节 PPARγ 表达，从而赋予对创伤性败血症的易感性。试验注册ClinicalTrials.gov，NCT01713205。2012年10月18日登记，追溯登记。因此赋予对创伤性败血症的易感性。试验注册ClinicalTrials.gov，NCT01713205。2012年10月18日登记，追溯登记。因此赋予对创伤性败血症的易感性。试验注册ClinicalTrials.gov，NCT01713205。2012年10月18日登记，追溯登记。