Genetic Background Analysis of Protein C Deficiency Demonstrates a Recurrent Mutation Associated with Venous Thrombosis in Chinese Population

Abstract

BackgroundProtein 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.MethodsThirty-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.ResultsA 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.ConclusionsThis 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.

Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

“…In China, two recent studies found two predominant mutations of PROC, Lys173del and Arg189Trp, both in VTE patients and in the general population (Table 3). 32,33 In our study, Lys173del and Arg189Trp were observed in three and one patients, respectively, but not in the population group ( Figure 1A). Of note, all three patients with heterozygous Lys173del also had another PROC mutation (Table 2).…”

Genetic characterization of antithrombin, protein C and protein S deficiencies in Polish patients

“…34 The p. Cys64Tyr variant eliminates cysteine residues, which might result in aberrant protein multimerization or creation of the high -molecular--weight protein complex and impaired protein secretion. 33,35 A similar mutation in the same codon but with a different amino acid change (p.Cys64Gly) has been reported by Kuismanen et al 35 in a family from Finland, with a history of thrombosis and type I PC deficiency. The next new p.Cys175Arg variant within the PROC gene is located in the epidermal growth factor (EGF)-2 domain and might affect PC stability.…”

“…These variants may potentially affect binding of the substrate. 33 Moreover, in the missense variant at position 387, cysteine is replaced by tyrosine, which may be important for disulfide bond formation, associated with protein stabilization. In turn, the p.Cys64Tyr variant of the PROC gene is located in the γ -carboxyglutamic domain within the PC structure.…”

Association between genetic polymorphisms and deep vein thrombosis in a Chinese population

“…Several previous studies have revealed a relationship between DVT and genetic mutations in protein C, protein S, and antithrombin [24][25][26], which suggests that anticoagulant defects are the main cause of Asian thrombophilia. However, genetic polymorphisms of other natural anticoagulants did not attract enough attention.…”