OBJECTIVETo study the molecular pathogenesis of protein C (PC) deficiency in a patient with pulmonary embolism and in his family members.

METHODSAnticoagulated blood samples were collected from the proband and his family members to detect PC, PS and AT activities. PC antigen level was measured using ELISA. The genomic DNA was extracted to amplify all the 9 exons and their flanking sequences of PC gene using PCR, and the PCR products were sequenced. The mutated exons identified were amplified and sequenced for the other family members.

RESULTSThe proband and his parents and sister were identified as carriers of PC gene mutation, which led to type II PC deficiency. Sequencing of the proband's PC gene showed two heterozygous point mutations in exon 3 (G5540A) and exon 7 (C10230T) to cause compound heterozygous mutations of PC E29K and PC R147W, which were inherited from his father and mother, respectively. His sister was a heterozygote of PC R147W.

CONCLUSIONThe proband is a compourd heterozygous mutations carrier of PC E29K and PC147W. PC E29K is a novel PC mutation, and PC R147W is a reported PC gene mutation seen in patients with type II hereditary PC deficiency and recurrent thrombosis.

Adolescent ; Base Sequence ; Heterozygote ; Humans ; Male ; Molecular Sequence Data ; Pedigree ; Point Mutation ; Protein C ; genetics ; Protein C Deficiency ; complications ; genetics ; pathology ; Pulmonary Embolism ; etiology ; genetics

AIMTo investigate the dynamic changes of Egr-1 expression in the lungs of acute pulmonary embolism of rats by infusion of autoblood thrombs.

METHODSThe model of pulmonary embolism by infusion of autoblood thrombs in the pulmonary artery of rats was established and the mean pulmonary arterial pressure was continuously monitored by computer, and the results were evaluated by lung perfusion scan and pathological changes. Expression of Egr-1 proteinum and mRNA were measured by immunohistochemistry and reverse transcription polymerase chain reaction.

RESULTSThe mPAP of rats was increased significantly after infusion of autoblood thrombs at the half hour, and reached high level at the second hour, then remained the high level to four hours compared with group control at the same time point (P < 0.01). ECT image was showed significantly filling defect after infusion of autoblood thrombs at the first hour. The infused thromb was witnessed by hematoxylin and eosin stain. In the tracheal epithelium cells, alveolar epithelium cells and vascular smooth muscle cells of embolism rats, Egr-1 protein expression was increased significantly after embolization at the second hour compared with group control at the same time point (P<0.01), and was decreased slowly at the fourth hour. Egr-1 mRNA expression was showed the similar changes.

CONCLUSIONExpression of Egr-1 was low level in group control, but increased significantly after infusion of autoblood thromb at the second hour in the specificity of cells, suggesting that Egr-1 expression might be an important link of pathological changes in the acute pulmonary embolism.

Animals ; Early Growth Response Protein 1 ; genetics ; metabolism ; Gene Expression ; Lung ; metabolism ; Male ; Pulmonary Embolism ; genetics ; metabolism ; pathology ; RNA, Messenger ; genetics ; Rats ; Rats, Sprague-Dawley

Objective: To explore the clinical characteristics and genotype of PROS1 gene related hereditary protein S deficiency (PSD) with the onset of pulmonary embolism in children. Methods: A family with pulmonary embolism was diagnosed as hereditary PSD in the Department of Pediatrics of Peking University First Hospital in November 2020, and the clinical data, including clinical manifestations, laboratory tests, imaging and genetic results, were collected for a retrospective research. The family members were also screened for protein S activity and PROS1 gene mutations. A literature search with "PROS1" "protein S deficiency" "homozygous" and "complex heterozygous" as key words was conducted at PubMed, China National Knowledge Infrastructure, and Wanfang Data Knowledge Service Platform (up to October 2021). Case reports of patients with PROS1 gene homozygous or complex heterozygous variants and related clinical features, protein S activity, and genotype were reviewed and analyzed. Results: The proband, a 14-year-old girl, was admitted to the hospital for a 9-day history of coughing and a 4-day history of chest pain in November 2020. After admission, laboratory tests showed that D-dimer was 8.38 mg/L (reference:<0.24 mg/L). An urgent CT pulmonary angiography confirmed bilateral pulmonary embolism and right lower pulmonary infarction, while an ultrasonography showed deep vein thrombosis in her left leg. Further examination revealed that protein S activity was less than 10%. The proband's second sister, a 12-year-old girl, was admitted to the hospital in December 2020. Her protein S activity was 8% and an ultrasonography showed deep vein thrombosis in her right leg. The protein S activity of the proband's father and mother were 36% and 26%, respectively. Trio-whole-exome sequencing detected compound heterozygous PROS1 gene variants (c.-168C>T and c.200A>C (p.E67A)) for the proband and her second sister, that were inherited from her father and mother, respectively. The proband's third sister's protein S activity was 28%; she and the proband's grandfather both carried c.200A>C (p.E67A) variants. The proband and her younger sister were treated with rivaroxaban and responded well during the 3-month follow-up. A total of 1 Chinese report in literature and 18 English literature were retrieved and 14 patients with protein S deficiency caused by homozygous or complex heterozygous variants of PROS1 gene were enrolled, including 8 male and 6 female patients. The ages ranged from 4 days to 35 years. Three patients experienced fulminant purpura or severe intracranial hemorrhage in early neonatal-period, while the remaining 11 patients developed venous thromboembolism in adolescence. Protein S activity was examined in 11 patients, and all showed less than 10% of activity. Missense variants was the most common type of gene variants. Conclusions: For children with pulmonary embolism, if there are no clear risk factors for thrombosis, hereditary protein S deficiency should be considered, and protein S activity should be examined before oral anticoagulant drugs. If protein S activity is less than 10%, protein S deficiency caused by homozygous or complex heterozygous variants should be considered.
Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Infant, Newborn ; Male ; Pedigree ; Protein S/genetics* ; Protein S Deficiency/genetics* ; Pulmonary Embolism/genetics* ; Retrospective Studies

PURPOSE: Hereditary thrombophilia (HT) is a major risk factor for idiopathic pulmonary embolism (iPE) and shows different prevalence among ethnic groups. The prevalence and clinical characteristics of HT in Korean patients with iPE were investigated. MATERIALS AND METHODS: Patients with PE on computed tomography (CT) scan were recruited, and those with malignancy were excluded. Patients were divided into iPE and provoked PE (pPE) groups. The presence of HT in the iPE group was assessed by DNA sequencing of the corresponding gene in patients who had low levels of natural anticoagulants. The clinical characteristics of iPE with HT (iPE/HT+) were compared with those of iPE without HT (iPE/HT-) and pPE. RESULTS: Out of 161 patients, 84 patients had iPE and 77 patients had pPE. Among 54 patients in the iPE group whose coagulation profiles were tested, 28 patients were diagnosed with HT (51.9%; 28/54). Compared with the iPE/HT- and pPE groups, the iPE/HT+ group showed the highest proportion of male patients (71.4%; p<0.001); the youngest mean age (44+/-14 years; p<0.001); and the highest frequencies for history of venous thromboembolism (64.3%; p<0.001), concurrent deep vein thrombosis (75.0%; p=0.021), and adverse clinical outcomes (42.9%, p<0.001). Protein C deficiency was the most common HT. On molecular genetic tests, causative mutation was identified in 13 patients. CONCLUSION: In this study of Korean patients, about half of the patients with iPE had HT. Patients with iPE and HT were mostly young males with deep venous thrombosis (DVT), previous venous thromboembolism (VTE), and frequent adverse clinical outcomes. Therefore, Korean patients with iPE should be tested for HT.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group ; Female ; Humans ; Korea ; Male ; Middle Aged ; Mutation ; Pulmonary Embolism/diagnosis/genetics/*radiography ; Thrombophilia/diagnosis/genetics/*radiography ; Young Adult

OBJECTIVESchimke immuno-osseous dysplasia (SIOD), is an autosomal recessive inherited disease caused by SMARCAL1 (MIM:20606622) mutations, while in about half of the patients no any mutation in SMARCAL1 could be found. This disease involves multiple systems and is characterized by short and dissymmetric stature with spondyloepiphyseal dysplasia, progressive renal failure, lymphopenia with recurrent infections, and hyperpigmented macules. This study aimed to analyze SMARCAL1 gene of 2 unrelated suspected SIOD children, to make definite diagnosis, and find more SMARCAL1 mutation types of Chinese SIOD.

METHODTwo suspected Chinese Han male SIOD children who visited our hospital from 2008 to 2014, aged 3 y 6 m and 7 y 8 m, both were short and had spondyloepiphyseal dysplasia, progressive renal failure, lymphopenia with recurrent infections. After informed consent, they and their parents's DNA were extracted from blood. PCRs for all 16 exons of SMARCAL1 were performed and PCR products were purified by 2% gel electrophoresis and sequenced directly. Pathogenicity of missense variations was confirmed by SIFT and sequencing SMARCAL1 of fifty normal controls.

RESULT(1) Four gene variations were found in the two children: Two reported missense mutations c.1129G>C, p.Glu377Gln and c.1933C>T, p. Arg645Cys. Two splicing mutations c.1334+1G>A and c.2142-1 G>A were detected. (2) c.1129G>C, p.Glu377Gln were reported as a disease-causing mutations before, but it was an single nucleotide polymorphism (SNP) which was found in 15 of 50 normal controls. (3) Two novel splicing mutations were found in this study: c.1334+1G>A and c.2142-1 G>A.

CONCLUSION(1) We detected 3 disease-causing mutations in 2 SIOD children by SMARCAL1 gene analysis, while 2 splicing mutations were novel mutations. (2) c.1129G>C, p.Glu377Gln was a SNP but not a disease-causing mutation at least in Chinese population.

Arteriosclerosis ; complications ; genetics ; Base Sequence ; Child ; Child, Preschool ; DNA Helicases ; genetics ; Exons ; Humans ; Immunologic Deficiency Syndromes ; complications ; genetics ; Lymphopenia ; Male ; Mutation ; Mutation, Missense ; Nephrotic Syndrome ; complications ; genetics ; Osteochondrodysplasias ; complications ; congenital ; genetics ; Polymorphism, Single Nucleotide ; Pulmonary Embolism ; complications ; genetics ; Renal Insufficiency

Protein C is an important physiological anticoagulant factor. Protein C deficiency has been linked to venous thrombosis at unusual sites, including the cerebral and mesenteric veins. Hereditary protein C deficiency is inherited primarily as an autosomal dominant trait with incomplete penetrance. Protein C and S deficiencies are known to increase the risk of venous thrombosis and pulmonary thromboembolism. Testing for protein C levels and function is necessary for the detection of both type I and type II protein C deficiency. In this article, we report a case of pulmonary embolism and mesentery ischemia due to type 1 protein C deficiency.
Colonoscopy ; Humans ; Ischemia/*diagnosis/etiology ; Magnetic Resonance Angiography ; Male ; Mesenteric Veins ; Middle Aged ; Protein C Deficiency/*complications/genetics ; Pulmonary Embolism/*diagnosis/etiology/radiography ; Tomography, X-Ray Computed

OBJECTIVETo determine the prevalence of beta-fibrinogen gene -455G/A, -148C/T polymorphisms in Chinese Han population and to investigate whether they were associated with pulmonary thromboembolism (PTE).

METHODSThe subjects consisted of 101 patients with PTE and 101 healthy controls matched with age and sex, from the same geographic area. All patients were diagnosed by high probability of lung ventilation/perfusion scan and/or multi-slice CT pulmonary angiography as well as medical history and clinical manifestations. Genome DNA was extracted from whole blood using KI-phenol-chloroform. Genotypes and allele frequencies of fibrinogen beta gene -455G/A, -148C/T polymorphisms were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Restriction enzyme HaeIII and HindIII digestion were used for detecting -455G/A, -148C/T polymorphisms respectively.

RESULTSRegarding fibrinogen beta gene -455G/A and -148C/, the allele frequencies G and A of fibrinogen beta -455 in the controls were 0.931, 0.069 while C and T of -148 were 0.777, 0.223 respectively, which were in good agreement with Hardy-Weinberg equilibrium. There was significant difference of -455G/A genotype frequencies distribution of AA, GA, GG between cases and in controls respectively, but no significant difference was found in the -148C/T polymorphisms. The frequencies of mutation allele -455A were 0.193, 0.169 in cases and in controls with P < 0.05 but there was no statistically significant difference of -148T allele. The presence of A allele of fibrinogen beta -455 was found to be a greater risk factor in cases than in controls. The odds ratio (OR) of GA and GA + AA were 3.723 (1.786 - 7.759), 3.749 (1.842 - 7.630), respectively. When compared with GG genotype, the P value was 0.0001.

CONCLUSIONThere was a complete linkage disequilibrium between fibrinogen beta -148C/T and -455G/A found. The frequencies of -455A, alleles in PTE disease were apparently higher than that of healthy adults but there was no difference in -148T alleles.

Asian Continental Ancestry Group ; genetics ; Case-Control Studies ; China ; Fibrinogen ; genetics ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Linkage Disequilibrium ; Odds Ratio ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Pulmonary Embolism ; genetics ; Risk Factors

OBJECTIVETo evaluate the effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms on Warfarin maintenance dose variation in Chinese Han Population.

METHODSFour hundred eighty-eight patients with prosthetic heart valves, atrial fibrillation or pulmonary thromboembolism and achieved stable Warfarin dose were enrolled. TaqMan probe or direct sequencing were used to genotype Y9VKORC1, CYP2C9, GGCX, EPHX1 and CYP4F2 gene polymorphisms. Demographic characteristics, stable therapeutic dose of Warfarin and concomitant medications were collected for all patients. The effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms, demographic characteristics and concomitant medications on Warfarin daily maintenance dose were analyzed with statistical method.

RESULTSVKORC1 and CYP2C9 gene polymorphisms could explain more than 50% Warfarin maintenance dose variation in recruited patients, while CYP4F2 gene polymorphisms could only explain 1%. GGCX, PROC and EPHX1 gene polymorphisms had no impact no Warfarin maintenance dose. VKORC1 and CYP2C9 gene polymorphisms have a greater impact on Warfarin maintenance dose compared with demographic characteristics and concomitant medications.

CONCLUSIONVKORC1 and CYP2C9 gene polymorphisms have a significant impact on Warfarin maintenance dose in Chinese Han population.

Adult ; Aged ; Aryl Hydrocarbon Hydroxylases ; genetics ; Asian Continental Ancestry Group ; ethnology ; genetics ; Atrial Fibrillation ; drug therapy ; ethnology ; genetics ; Cytochrome P-450 CYP2C9 ; Cytochrome P-450 Enzyme System ; genetics ; Cytochrome P450 Family 4 ; Dose-Response Relationship, Drug ; Epoxide Hydrolases ; genetics ; Female ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Protein C ; genetics ; Pulmonary Embolism ; drug therapy ; ethnology ; genetics ; Treatment Outcome ; Vitamin K Epoxide Reductases ; genetics ; Warfarin ; administration & dosage ; Young Adult

No abstract available.
Aged ; Anticoagulants/therapeutic use ; DNA Mutational Analysis ; Echocardiography ; Genetic Predisposition to Disease ; Homozygote ; Humans ; Hyperhomocysteinemia/blood/complications/diagnosis/drug therapy/*genetics ; Male ; Methylenetetrahydrofolate Reductase (NADPH2)/*genetics ; *Mutation ; Phenotype ; Pulmonary Embolism/blood/diagnosis/drug therapy/*etiology ; Severity of Illness Index ; Thrombolytic Therapy ; Tomography, X-Ray Computed ; Treatment Outcome ; Vitamins/therapeutic use

Pharmacogenetic testing for clinical applications is steadily increasing. Correct and adequate use of pharmacogenetic tests is important to reduce unnecessary medical costs and adverse patient outcomes. This document contains recommended pharmacogenetic testing guidelines for clinical application, interpretation, and result reporting through a literature review and evidence-based expert opinions for the clinical pharmacogenetic testing covered by public medical insurance in Korea. This document aims to improve the utility of pharmacogenetic testing in routine clinical settings.
Anticoagulants/therapeutic use ; Antidepressive Agents/therapeutic use ; Antimetabolites, Antineoplastic/therapeutic use ; Antitubercular Agents/therapeutic use ; Arylamine N-Acetyltransferase/genetics ; Coronary Artery Disease/drug therapy/genetics ; Cytochrome P-450 CYP2C19/genetics ; Cytochrome P-450 CYP2C9/genetics ; Cytochrome P-450 CYP2D6/genetics ; Depressive Disorder/drug therapy/genetics ; Genotype ; Isoniazid/therapeutic use ; Laboratories, Hospital/standards ; Methyltransferases/genetics ; Pharmacogenomic Testing/*methods/standards ; Platelet Aggregation Inhibitors/therapeutic use ; Pulmonary Embolism/drug therapy/genetics ; Ticlopidine/analogs & derivatives/therapeutic use ; Tuberculosis/drug therapy/genetics ; Vitamin K Epoxide Reductases/genetics ; Warfarin/therapeutic use