title: Genetic variation in the tissue factor gene is associated with clinical outcome in severe sepsis patients.
abstract: BACKGROUND
  Activation of inflammation and coagulation was closely related and mutually interdependent in sepsis. Tissue factor (TF) and its endogenous inhibitor, tissue factor pathway inhibitor (TFPI) was the main regulators of the initiation of coagulation process. Altered plasma levels of TF and TFPI have been related to worse outcome in sepsis. The objective of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the TF and TFPI genes were associated with risk and outcome for patients with severe sepsis.
  
  
  METHODS
  Seventeen SNPs in TF and TFPI were genotyped in samples of sepsis (n =577) and severe sepsis patients (n =476), and tested for association in this case-control collection. We then investigated correlation between the associated SNPs and the mRNA expression, and protein level of the corresponding gene. The mRNA levels of TF were determined using real-time quantitative reverse transcription-polymerase chain reaction and the soluble plasma levels of TF were measured using enzyme linked immunosorbent assay (ELISA) method.
  
  
  RESULTS
  Association analysis revealed that three TF SNPs in perfect linkage disequilibrium, rs1361600, rs3917615 and rs958587, were significantly associated with outcome of severe sepsis. G allele frequency of rs1361600 in survivor patients was significantly higher than that in nonsurvivor severe sepsis patients (P =4.91 × 10(-5), odds ratio (OR) =0.48, 95% confidence interval (CI) 0.33 to 0.69). The association remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. Lipopolysaccharide-induced TF-mRNA expression levels in peripheral blood mononuclear cells from subjects carrying rs1361600 AG and GG genotypes, were significantly lower than those subjects carrying AA genotype (P =0.0012). Moreover, severe sepsis patients of GG and GA genotypes showed lower serum levels of TF than patients with AA genotype (P adj =0.02). The plasma levels of TF were also associated with outcome of severe sepsis patients (P adj =0.01). However, genotype and allele analyses did not show any significant difference between sepsis and severe sepsis patients.
  
  
  CONCLUSIONS
  Our findings indicate that common genetic variation in TF was significantly associated with outcome of severe sepsis in Chinese Han population.
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. shi.dongwei@zs-hospital.sh.cn.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Shi
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. zhenjusong@yahoo.com.
authors.forename: Zhenju
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. yin.jun@zs-hospital.sh.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. xue.mingming@zs-hospital.sh.cn.
authors.forename: Mingming
authors.initials: M
authors.lastname: Xue
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. yao.chenling@zs-hospital.sh.cn.
authors.forename: Chenling
authors.initials: C
authors.lastname: Yao
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. sun.zhan@zs-hospital.sh.cn.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. shaomian11@hotmail.com.
authors.forename: Mian
authors.initials: M
authors.lastname: Shao
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. deng.zhi@zs-hospital.sh.cn.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. zhang.yaping@zs-hospital.sh.cn.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. tao.zhengang@zs-hospital.sh.cn.
authors.forename: Zhengang
authors.initials: Z
authors.lastname: Tao
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. sun.si@zs-hospital.sh.cn.
authors.forename: Si
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. zhang.jin@zs-hospital.sh.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. xing.lingyu@zs-hospital.sh.cn.
authors.forename: Lingyu
authors.initials: L
authors.lastname: Xing
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. dong.zhimin@zs-hospital.sh.cn.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. wang.yuxin@zs-hospital.sh.cn.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China. tong.chaoyang@zs-hospital.sh.cn.
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Tong
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018805:Sepsis / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D013925:Thromboplastin / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D013925:Thromboplastin