| Background:Liddle syndrome is an autosomal-dominant inheritance disease, caused by mutations in an epithelial sodium channel (ENaC). Most reported mutations in patients with Liddle syndrome are either missense or frameshift mutations that either delete or alter the conserved proline-rich PY motif (PPPXY sequence) localized at the C-terminal ends of the β and γ subunits of ENaC. Typical Liddle syndrome is characterized by early onset of hypokalemic hypertension with low plasma renin activity (PRA) and low serum aldosterone level, but patients with Liddle syndrome show marked phenotypic variation in blood pressure, serum potassium and other clinical manifestations.Objective:Analyzed the correlation of genotype-phenotype in two Chinese families with Liddle syndrome.Methods:The sequence of C-terminus of SCNN1B and SCNN1G were screened in the two families with likely Liddle syndrome, and there clinical information were collected. In addition to hypertension and hypokalemia, one of the two pedigrees had sudden death in their family members, so the exons of428reported genes-related to cardiovascular diseases were screened as well in the family. We also compared the phenotypes among the patients carrying the identical mutation in our study and in previous studiesResults:A heterozygous PR566X nonsense mutation was found in the proband-1in the first pedigree, and the proband’s sister and father. They showed mild phenotype with hypertension and hypokalemia, and the blood pressure was under control by calcium channel bloker and ENac blocker. Two of the four previous studies report that the mutation causes severe phenotype, even die of stroke in their thirties, while the other two families showed a mild clinical phenotype. In contrast, a heterozygous pR597PfrX607frameshift mutation was identified in the proband-2in the second pedigree, showing malignant phenotype including resistant hypertension, hypokalemia, and sever target organ damagement. Both the proband-2and the proband-2’s father had sudden death in their twenties. But the same mutation has been related to moderate phenotype in previous studies, in which blood pressure could been controlled by ENaC blocker and no early maglinant cardiovascular events. By screening of the exons in428cardiovascular disease-related genes, some missense and frameshift mutations were found other than SCNN1B, but most of them were also detected in the proband’s brother, who was a genetically unaffected member with normal phenotype. Genes with mutation-unique to the proband-2has not been associated with blood pressure by either function study or convincable association study.Conclusion:The phenotypes of Liddle syndrome are varied significantly even with the same mutation. The mechanisms why the same mutation causes very different phenotype need to be explored because intervention of these modifiers may change the disease course and prognosis accordingly. Background:Warfarin has remained the mainstay of oral anticoagulant therapy for the treatment and prevention of thromboembolism. However, management of warfarin therapy is challenging because of its narrow therapeutic index and wide inter-individual variability. Effect of warfarin could be influenced by many factors, incluing gender, age, body surface area, concominant drugs and foods. Also genetic variants could affect warfarin, many studies have shown that single nucleotide polymorphisms (SNPs) within CYP2C9and VKORC1genes are related to warfarin dose requirement. CYP4F2rs2108622(V433M) was found to be associated with warfarin dose in3independent Caucasian cohorts. Food and Drug Administration has changed the drug label for warfarin and include the statement,"The patient’s CYP2C9and VKORC1genotype information, when available, can assist in selection of the starting dose." Previous studies constructed many algorithms to predict the warfarin maintenance dose in Chinese individuals. However, they frequently used relatively small populations (<400subjects) except in two studies where one included845from Southern China, and the other included641from Central ChinaObjectives:The objective of the current study was to assess these genetic determinants of the warfarin maintenance dose and to construct an algorithm integrating common interference factors to predict the dose in a large population who lived in Northern China.Methods:This study enrolled800consenting patients with heart-valve replacements who were receiving long-term warfarin maintenance therapy,23related SNPs were genotyped. First, the associations of these SNPs with the warfarin maintenance dose were tested. Second, on the basis of genotypes associated with the warfarin maintenance dose, an algorithm integrating common non-genetic factors was constructed to predict the dose in the derivation cohort (70%of the whole cohort), and was assessed in the validation cohort (30%of the whole cohort).Results:Only VKORC1and CYP2C9SNPs were observed to be significantly associated with warfarin dose. The relationship between gene CYP4F2rs2108622and warfarin dose was not significant in the univariate analysis(P=0.152), however, the P-value was0.01in the final multiple regression model. Generally, in the derivation cohort (n=551), warfarin dose variability was influenced, in decreasing order, by VKORC1rs7294(27.3%), CYP2C9*3(7.0%), body surface area(4.2%), age(2.7%), target INR(1.4%), CYP4F2rs2108622(0.7%), amiodarone use(0.6%), diabetes mellitus(0.6%), and digoxin use(0.5%), which account for45.1%of the warfarin dose variability. In the validation cohort (n=236), the actual maintenance dose was significantly correlated with predicted dose (r=0.609, P<0.001). Furthermore, our algorithm demonstrated the best predictor in northern Chinese people compared with the other two algorithms derived from southern Chinese and central Chinese populations.Conclusions:Our algorithm could improve the personalized management of warfarin use in Northern Chinese patients. |
PDF Full Text Request