title: Genetic background analysis of protein C deficiency demonstrates a recurrent mutation associated with venous thrombosis in Chinese population.
abstract: BACKGROUND
  Protein C (PC) is one of the most important physiological inhibitors of coagulation proteases. Hereditary PC deficiency causes a predisposition to venous thrombosis (VT). The genetic characteristics of PC deficiency in the Chinese population remain unknown.
  
  
  METHODS
  Thirty-four unrelated probands diagnosed with hereditary PC deficiency were investigated. PC activity and antigen levels were measured. Mutation analysis was performed by sequencing the PROC gene. In silico analyses, including PolyPhen-2, SIFT, multiple sequence alignment, splicing prediction, and protein molecular modeling were performed to predict the consequences of each variant identified. One recurrent mutation and its relative risk for thrombosis in relatives were analyzed in 11 families. The recurrent mutation was subsequently detected in a case (VT patients)-control study, and the adjusted odds ratio (OR) for VT risk was calculated by logistic regression analysis.
  
  
  RESULTS
  A total of 18 different mutations, including 12 novel variants, were identified. One common mutation, PROC c.565C>T (rs146922325:C>T), was found in 17 of the 34 probands. The family study showed that first-degree relatives bearing this variant had an 8.8-fold (95%CI = 1.1-71.6) increased risk of venous thrombosis. The case-control (1003 vs. 1031) study identified this mutation in 5.88% patients and in 0.87% controls, respectively. The mutant allele conferred a high predisposition to venous thrombosis (adjusted OR = 7.34, 95%CI = 3.61-14.94). The plasma PC activity and antigen levels in heterozygotes were 51.73±6.92 U/dl and 75.17±4.84 U/dl, respectively.
  
  
  CONCLUSIONS
  This is the first study on the genetic background of PC deficiency in the Chinese population. The PROC c.565C>T mutation is the most frequent cause of PC deficiency as well as a prevalent risk factor for VT in Chinese individuals. The inclusion of this variant in routine thrombophilic detection may improve the diagnosis and prevention of venous thrombosis.
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.forename: Heng
authors.initials: H
authors.lastname: Mei
authors.forename: Huafang
authors.initials: H
authors.lastname: Wang
authors.forename: Xuan
authors.initials: X
authors.lastname: Lu
authors.forename: Jianming
authors.initials: J
authors.lastname: Yu
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D006801:Humans; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D011486:Protein C / Q000737:chemistry / Q000235:genetics*; D020151:Protein C Deficiency / Q000150:complications* / Q000235:genetics*; D016415:Sequence Alignment; D020246:Venous Thrombosis / Q000150:complications* / Q000235:genetics*; D055815:Young Adult
chemical_list: D011486:Protein C