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中华危重症医学杂志(电子版) ›› 2021, Vol. 14 ›› Issue (04) : 269 -274. doi: 10.3877/cma.j.issn.1674-6880.2021.04.002

论著

血栓调节蛋白基因多态性与肺栓塞的风险评估
王娜1, 褚娇娇1, 张鹏1, 夏岑峰1,†()   
  1. 1. 750004　银川，宁夏医科大学总医院心脑血管病医院呼吸与危重症医学科
  • 收稿日期:2021-02-25 出版日期:2021-08-31
  • 通信作者: 夏岑峰
  • 基金资助:
    宁夏医科大学科学研究基金资助项目(XM2016081)

Risk assessment of thrombomodulin gene polymorphism and pulmonary embolism

Na Wang1, Jiaojiao Chu1, Peng Zhang1, Cenfeng Xia1,†()   

  1. 1. Department of Respiratory and Critical Care Medicine, Cardiocerebral Vascular Disease Hospital, General Hospital of Ningxia Medical University, Yinchuan 750004, China
  • Received:2021-02-25 Published:2021-08-31
  • Corresponding author: Cenfeng Xia
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引用本文：

王娜, 褚娇娇, 张鹏, 夏岑峰. 血栓调节蛋白基因多态性与肺栓塞的风险评估[J]. 中华危重症医学杂志(电子版), 2021, 14(04): 269-274.

Na Wang, Jiaojiao Chu, Peng Zhang, Cenfeng Xia. Risk assessment of thrombomodulin gene polymorphism and pulmonary embolism[J]. Chinese Journal of Critical Care Medicine(Electronic Edition), 2021, 14(04): 269-274.

目的

探讨血栓调节蛋白（TM）THBD基因rs1042579和rs3176123位点的单核苷酸多态性（SNP）与肺栓塞发生风险的相关性。

方法

选取100例栓塞患者（肺栓塞组）及100例健康志愿者（对照组）作为研究对象，提取研究对象全血基因组DNA，对THBD基因上的两个SNP位点rs1042579和rs3176123进行高分辨率熔解曲线检测，比较两组患者可溶性TM（sTM）水平、rs1042579及rs3176123基因型分布，采用Logistic回归分析rs1042579及rs3176123位点各基因型及等位基因与肺栓塞发生风险的相关性。

结果

肺栓塞组的sTM水平明显高于对照组患者[（592 ± 372）μg/L vs. （480 ± 250）μg/L，t = 2.487，P = 0.014]，且肺栓塞组与对照组患者rs1042579（CC/CT/TT）[57/39/4 vs. 85/15/0，χ2 = 20.188，P<0.001]及rs3176123（AA/AC/CC）[47/37/16 vs. 72/21/7，χ2 = 13.188，P = 0.001]基因型分布的比较，差异均有统计学意义。rs1042579位点的基因型CT[比值比（OR）= 2.600，95%置信区间（CI）（1.535，4.404），P<0.001]和等位基因T[OR = 3.133，95%CI（1.813，5.416），P<0.001]为肺栓塞的危险因素，基因型CC[OR = 0.671，95%CI（0.555，0.810），P<0.001]和等位基因C[OR = 0.827，95%CI（0.759，0.902），P<0.001]则为肺栓塞发生的保护因素。rs3176123位点的基因型AC [OR = 1.762，95%CI（1.114，2.786），P = 0.013]及等位基因C [OR = 1.260，95%CI（1.118，1.419），P<0.001]均是肺栓塞的危险因素，基因型AA [OR = 0.653，95%CI（0.513，0.831），P<0.001]及等位基因A [OR = 0.507，95%CI（0.355，0.724），P<0.001]均是肺栓塞的保护因素。

结论

中国人群THBD基因中rs1042579位点基因型CT及等位基因T和rs3176123位点基因型AC及等位基因C均为肺栓塞发生的危险因素。

关键词: 肺栓塞, 血栓调节蛋白, 多态性, 单核苷酸
Objective

To investigate the correlation between single nucleotide polymorphism (SNP) in THBD rs1042579 and rs3176123 sites of the thrombomodulin (TM) and the risk for pulmonary embolism.

Methods

Totally 100 patients with pulmonary embolism (pulmonary embolism group) and 100 healthy volunteers (control group) were enrolled in this study. Their genomic DNA was extracted. A high resolution melting test was used to determine the polymorphism of rs1042579 and rs3176123 sites in the THBD gene. The level of soluble TM (sTM) and the distribution of rs1042579 and rs3176123 genotypes were compared between the two groups. The correlation between genotypes and alleles in rs1042579 and rs3176123 sites and the risk of pulmonary embolism was analyzed by Logistic regression.

Results

The level of sTM in the pulmonary embolism group was higher than that in the control group [(592 ± 372) μg/L vs. (480 ± 250) μg/L, t= 2.487, P= 0.014]. The genotype distribution of rs1042579 (CC/CT/TT) [57/39/4 vs. 85/15/0, χ2 = 20.188, P < 0.001] and rs3176123 (AA/AC/CC) [47/37/16 vs. 72/21/7, χ2= 13.188, P= 0.001] showed significant differences between the pulmonary embolism group and control group. The genotype CT [odds ratio (OR)= 2.600, 95% confidence interval (CI) (1.535, 4.404), P < 0.001] and allele T [OR= 3.133, 95%CI (1.813, 5.416), P < 0.001] of rs1042579 site were risk factors for pulmonary embolism, while the genotype CC [OR= 0.671, 95%CI (0.555, 0.810), P < 0.001] and allele C [OR= 0.827, 95%CI (0.759, 0.902), P < 0.001] were its protective factors. The genotype AC [OR= 1.762, 95%CI (1.114, 2.786), P= 0.013] and allele C [OR= 1.260, 95%CI (1.118, 1.419), P < 0.001] of rs3176123 site were risk factors for pulmonary embolism, while the genotype AA [OR= 0.653, 95%CI (0.513, 0.831), P < 0.001] and allele A [OR= 0.507, 95%CI (0.355, 0.724), P < 0.001] were its protective factors.

Conclusion

The genotype CT and allele T of rs1042579 site and the genotype AC and allele C of rs3176123 site in the THBD gene of Chinese population are risk factors for pulmonary embolism.

Key words: Pulmonary embolism, Thrombomodulin, Polymorphism, single nucleotide
表1 突变位点引物序列
基因 引物序列（5’→3’） 产物长度(bp) GeneBank编号
rs1042579 上游引物：CACAACCTCCCCGGTACCTTC 70 NM_000361.2:c.1418 C > T
  下游引物：CCACCTTGCCGGAGTCACA    
rs3176123 上游引物：GACAGTGTTGAAAATGTTCAGAAGG 91 NM_000361.2:c.1001 A > C
  下游引物：ACTGTCTCCTGGGAGGTGTT    
表2 肺栓塞组与对照组一般资料的比较（ ± s）
组别 例数 男/女（例） 年龄（岁） sTM浓度(μg/L) rs1042579(CC/CT/TT,例) rs3176123(AA/AC/CC,例)
肺栓塞组 100 48/52 62 ± 11 592 ± 372 57/39/4 47/37/16
对照组 100 53/47 60 ± 11 480 ± 250 85/15/0 72/21/7
t/χ2值   0.500 0.845 2.487 20.188 13.188
P值   0.479 0.399 0.014 <0.001 0.001
图1 HRM技术对rs1042579和rs3176123位点的基因分型结果图
表3 rs1042579基因型和等位基因在肺栓塞组及对照组中的分布及危险因素分析
基因分型 例数 肺栓塞组（例） 对照组（例） OR值 95%CI P值
基因型            
  CC 100 57 85 0.671 0.555~0.810 <0.001
  CT 100 39 15 2.600 1.535~4.404 <0.001
  TT 100 4 0 - - -
等位基因            
  C 200 153 185 0.827 0.759~0.902 <0.001
  T 200 47 15 3.133 1.813~5.416 <0.001
表4 rs3176123基因型和等位基因在肺栓塞组及对照组中的分布及危险因素分析
基因分型 例数 肺栓塞组（例） 对照组（例） OR值 95%CI P值
基因型            
  AA 100 47 72 0.653 0.513~0.831 <0.001
  AC 100 37 21 1.762 1.114~2.786 0.013
  CC 100 16 7 2.286 0.983~5.315 0.046
等位基因            
  A 200 131 165 0.507 0.355~0.724 <0.001
  C 200 69 35 1.260 1.118~1.419 <0.001
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