Analysis of phenotype and CYP4V2 gene variants in two pedigrees affected with Bietti crystalline corneoretinal dystrophy / 中华医学遗传学杂志

OBJECTIVE@#The CYP4V2 gene of two pedigrees affected with Bietti crystalline corneoretinal dystrophy was analyzed to indentify the cause of the disease and provide a basis for clinical diagnosis.@*METHODS@#The probands were subjected to next generation sequencing (NGS). Suspected variants were verified by Sanger sequencing. Pathogenicity of the variants were searched through relevant databases and PubMed by following the ACMG guidelines.@*RESULTS@#A homozygous variant in the CYP4V2 gene c. (802-8) _810delTCATACAGGTCATCGCTinsGC was detected in proband from pedigree 1, parents did not detect; CYP4V2 genes c. (802-8)_810delTCATACAGGTCATCGCTinsGC and c. 958 C>T (p.Arg320X) compound heterozygous variants existed in the proband of pedigree 2,both parents were variant carriers. The results of Sanger sequencing showed that the variant of CYP4V2 gene in the two families was consistent with the NGS sequencing. The c. (802-8)_810delTCATACAGGTCATCGCTinsGC of CYP4V2 gene was splicing variant, and both splicing variant and nonsense variant could produce truncated nonfunctional protein products. Based on standards and guidelines by American College of Medical Genetics and Genomics, the CYP4V2 genes c. (802-8)_810del TCATACAGGTCATCGCTinsGC and c. 958 C>T (p.Arg320X) were predicted to be pathogenic variants (PVS1+PS1+PM2+PM3).@*CONCLUSION@#The homozygous variant c. (802-8) _810delTCATACAGGTCATCGCTinsGC and the complex heterozygous variants c. (802-8) _810delTCATACAGGTCATCGCTinsGC and c.958C>T (p.Arg320X) in CYP4V2 gene are the cause of the disease in the probands of two pedigrees , respectively.

Verification of accuracy of warfarin stable dose prediction models in Shandong population / 中华医学遗传学杂志

OBJECTIVE@#To compare the accuracy of five warfarin-dosing algorithms and warfarin stable dose model (2.5 mg/day) for Shandong population.@*METHODS@#One hundred and twenty five patients who achieved stable warfarin dose were enrolled. Clinical and genetic data were used to evaluate the value of each algorithm by calculating the percentage of patients whose predicted warfarin dose was within 20% of the actual stable therapeutic dose and mean absolute error (MAE).@*RESULTS@#The frequency of patients with CYP2C9*1/*1, CYP2C9*1/*3 and CYP2C9*1/*2 genotype was 92.00%, 7.20%, 0.80%, respectively. That of VKORC1-1639 AA, AG and GG genotype was 82.40%, 15.20%, 2.40%, respectively. CYP4F2*1/*1, *1/*3, *3/*3 genotype was 50.40%, 39.20%, 10.40%, respectively. With the same genotypes for other loci, patients who carried at least one VKORC1-16398G mutant allele had increased warfarin stable daily dose compared with VKORC1-1639AA. Compared with CYP4F2*1/*1, those carrying at least one CYP4F2*3 mutant allele had warfarin stable daily dose increased by 5.9%-13.00%. The percentage of ideal prediction calculated from IWPC model (59.20%), Huang model (57.60%) and Ohno model (52.80%) were higher than others. The MAE were 0.35 (95%CI: 0.11-0.49), 0.15 (95%CI: 0.10-0.32), 0.39 (95%CI: 0.12-0.51), respectively.@*CONCLUSION@#The polymorphisms of CYP2C9, VKORC1 and CYP4F2 genes can influence the stable dose of warfarin in Shandong population. IWPC algorithm is suitable for guiding the use of warfarin in this population.

Bietti Crystalline Retinopathy Confirmed by Mutation of CYP4V2 Gene in a Korean Patient

No abstract available.

Influence of genetic polymorphisms and non-genetic factors on the maintenance dose of warfarin / 中华医学遗传学杂志

OBJECTIVE To assess the influence of genetic polymorphisms and non-genetic factors on warfarin maintenance dose variations in order to provide guidance for personalized use of warfarin. METHODS Two hundred patients from outpatient and inpatient with stable international normalized ratio(INR) were recruited. Clinical data and blood samples were collected. Genotypes of 4 genes involved in warfarin metabolic pathways were determined with Sanger sequencing. Based on statistical analysis of warfarin maintenance dosage, a mathematical model was established. RESULTS Among non-genetic factors, the age and height have significant influence in warfarin dosage. The dosage is negatively correlated with age but positively correlated with height. The difference in dosage for between the 20-year-old group and 60-year-old group has reached 1.81 mg/day, and that for between the 140 cm in height and 180 cm in height groups has reached 1.06 mg/day. VKORC1 -1639G/A, CYP2C9 430C/T, CYP2C9 1075A/C and CYP4F2 V433M polymorphisms have significant influence on stable warfarin dosage. The dosage for patients with wild type and mutant genotypes has varied from 0.35 mg/day to 0.84 mg/day. CONCLUSION Non-genetic factors and genetic polymorphisms play important roles in personalized variations of warfarin maintenance dose. The establishment of mathematical models considering multiple factors is helpful in evaluating the safety and effectiveness of warfarin dosage.

Establishment and preliminary validation of warfarin maintenance dose algorithm in Chinese Han Population / 中华心血管病杂志

<p><b>OBJECTIVES</b>To establish an algorithm to predict the warfarin maintenance dose in Chinese Han population and validate the accuracy of this algorithm.</p><p><b>METHODS</b>A total of 488 Chinese Han patients, hospitalized in Fuwai hospital and had a stable dose of warfarin and a target international normalized ratio (INR) of 1.5 to 3.0, were recruited. Indications for warfarin use included prosthetic heart valve, atrial fibrillation and pulmonary embolism. These patients were divided into derivation group (n = 323) and validation group (n = 165) according to the enrollment time. A warfarin maintenance dose algorithm was established based on genetic information, demographic characteristics and concomitant medications by multiple linear regression analysis in derivation group. In the validation group, we evaluated the accuracy of our algorithm by comparing the predicted dose with the actual dose.</p><p><b>RESULTS</b>Our algorithm included VKORC1-1639G > A, CYP2C9*3 and CYP4F2 genotype, age, Body hight, body weight, amiodarone and digoxin use (R(2) = 0.652, P < 0.001) .In the validation group, the average predicted dose by our algorithm had no statistical difference with the actual dose [(3.51 ± 1.03) mg vs. (3.53 ± 1.41) mg, P = 0.779]. Our algorithm identified 100 out of 165 (60.6%) patients in the validation group, whose predicted dose of warfarin was within 20% of the actual dose, and predicted warfarin dose was underestimated in 17.6% (29/165) patients and overestimated in 21.8% (36/165) patients.</p><p><b>CONCLUSION</b>Our algorithm based on VKORC1, CYP2C9 and CYP4F2 polymorphisms can help to predict the warfarin maintenance dose in Chinese Han Population.</p>

Influence of warfarin related genes and non- genetic factors on administrative dose in Shanghai area / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the distribution of Warfarin related genes and the relationship between genotype, gender, weight, age and the administrative dose of Warfarin in Shanghai area.</p><p><b>METHODS</b>The clinical data (including sex, age and administrative dose of Warfarin) of 214 patients with stable warfarin dose and the international normalized ratio (INR) between 1.5-3.0 were collected. Polymerase chain reaction-high resolution melting (PCR-HRM) technique was used to detect the single nucleotide polymorphisms (SNPs) of CYP2C9*2 rs1799853, CYP2C9*3 rs1057910, CYP4F2 rs2108622 and VKORC1 rs9934438. The associations of genotype data with clinical material, including gender, age, weight and warfarin dosage were analyzed.</p><p><b>RESULTS</b>Among 214 patients, 99.53% (213 cases) patients with CC (wild type) of CYP2C9*2 rs1799853 and only 1 case with CT (heterozygous mutation) ; 92.52% (198 cases) with AA (wild type), 7.48% (16 cases) with CA (heterozygous mutation) of CYP2C9*3rs1057910; about 57.94% (124 cases) with CC(wild type) of CYP4F2 rs2108622, the CT and TT (heterozygous and homozygotic mutation) accounted for 42.06% (90 cases). In SNP VKORC1 rs9934438, 82.71% (177cases) were TT (wild type), 17.29% (37 cases) CT (heterozygous mutation). There are no significant difference (P=0.0872) in patients with maintenance dose in CYP2C9*3 between AA and CA gene mutations[(2.816±1.055) mg/d vs (2.352±0.805)mg/d], and no significant difference (P=0.5954) of that in CYP4F2 between CC and CT+TT gene mutations [(2.736±1.062) mg/d vs (2.813±1.034) mg/d]; but the significant differences (P=0.0001) does exist in patients with maintenance dose in VKORC1 between TT and CT variants [(2.597±0.866) mg/d vs (3.660±1.350) mg/d]. The warfarin maintain dosage was negatively correlated with the average age (r=-0.9669) and positively correlated with the body weight (r=0.9022).</p><p><b>CONCLUSION</b>It is of great significance to detect the VKORC1 variants for warfarin dosage adjustment in Shanghai population. However, the detection of CYP2C9*2 and CYP4F2 polymorphisms had no significant associations for warfarin dosage adjustment.</p>

Impact of six genetic polymorphisms on Warfarin maintenance dose variation in Chinese Han population / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To evaluate the effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms on Warfarin maintenance dose variation in Chinese Han Population.</p><p><b>METHODS</b>Four 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.</p><p><b>RESULTS</b>VKORC1 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.</p><p><b>CONCLUSION</b>VKORC1 and CYP2C9 gene polymorphisms have a significant impact on Warfarin maintenance dose in Chinese Han population.</p>

Correlation analysis and identification of G421C in regulatory region of CYP4F2 gene with essential hypertension / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the correlation between G421C polymorphism in the regulatory region of CYP4F2 gene and essential hypertension and its molecular mechanism.</p><p><b>METHODS</b>Totally 196 hypertensive patients (hypertension group) and 219 normotensive subjects (control group) were genotyped by polymerase chain reaction-restriction fragment length polymorphism. The promoter activity with different alleles was evaluated by reporter assay. A Myb responsive element was identified using gel retardation assay.</p><p><b>RESULTS</b>Significant differences were found in distribution of genotype and allele frequency of G421C between hypertension group and control group (P < 0.05), and homozygous GG genotype was independently associated with hypertension after adjustment for age, gender, body mass index, and other risk factors (odds ratios 1.87, 95% CI 1.11-3.13, P < 0.05). 421G reporter construct showed decreased promoter activity compared with 421C reporter construct. 421G existed in Myb responsive element, whereas 421C damaged this motif.</p><p><b>CONCLUSION</b>G421C polymorphism in the regulatory region of CYP4F2 gene is correlated with essential hypertension. 421G allele inhibits transcription by binding affinity of Myb responsive element.</p>

Effects of ginkgolides on gene expression of hepatic cytochrome P-450 in rats / 中国中药杂志

<p><b>OBJECTIVE</b>To observe the effects of ginkgolides on gene expression of hepatic cytochrome P-450 in rats.</p><p><b>METHOD</b>Sprague-Dawley rats were administered ginkgolides (100 mg x kg(-1) body weight) through oral gavage once daily for four consecutive days. The level of gene expression in liver tissues was analyzed by competitive reverse transcription-polymerase chain reaction (competitive RT-PCR).</p><p><b>RESULT</b>A single and prospective band of CYP1A1, CYP1A2, CYP2B1/B2, CYP2C11, CYP2E1, CYP4A1 and cyclophilin was observed after polymerase chain reaction (PCR) when the reactive system of reverse transcription (RT) had no target RNA, which confirmed the competitor had a specific capacity to bind to the CYP or cyclophilin primer. CYP1A1 mRNA was not dectectable in the livers of untreated control rats and ginkgolides-treated rats. The levels of CYP2C11 and CYP2E1 were not changed by ginkgolides treatment. In contrast, the levels of gene expression for CYP1A2 and CYP2B1/B2 were decreased, however, the levels of gene expression for CYP3A1 and CYP4A1 in ginkgolides group were distinctly increased compared with the control.</p><p><b>CONCLUSION</b>A specific effect of ginkgolides on cytochrome P-450 gene expression was observed in this investigation. Ginkgolides had various effects on different cytochrome P-450 isoforms.</p>