Marfan Syndrome In The Fbn1, Tgfbr2 Genotype Phenotype Association Studies Of Statins On Vascular Endothelial Function Improvement Effect Of Clinical Meta-analysis

Introduction:Marfan syndrome (MFS) is an autosomal domlnantly inherited connective tissue disorder characterized by cardiovascular, ocular and skeletal manifestations. Mutations in the fibrillin-1gene(FBN1) and transforming growth factor beta receptors Ⅱ gene (TGFBR2) have been proved to associate with Marfan syndrome (MFS). The correlation between genotype and phenotype in MFS and MFS-like patients is poorly understood.The purpose of this study is to identify the mutation spectrum in55Chinese probands with MFS or MFS-like phenotypes, and to establish genotype-phenotype correlations.Methods:A total of60unrelated probands with a MFS or Marfan-like features and100unrelated individuals were enrolled. The skeletal, cardiovascular, ophthalmic and other clinical data of these probands were evaluated and collected. All of the coding exons were amplified and sequenced directly in all the enrolled subjects. Genotype-phenotype correlation analysis was performed in the probands after sequencing.Results:A total of30FBN1mutations were identified in30of our55probands, with a detection rate of54.5%. Patients who fulfill the Ghent criteria had a detection rate of71.8%(28/39) of FBN1mutation. All these mutations were confirmed to be absent in the unrelated controls. Among these30FBN1mutations, sixteen are missense mutations; twelve are nonsense mutations and2are frameshift mutations. Twenty eight of the30mutation carriers (28/30,93.3%) had a cardiovascular involvement, and21of them got major cardiovascular lesion phenotypes (21/28). Twenty eight mutation carriers had skeletal system lesions, and15fulfilled the major diagnosis criteria. Twenty mutation carriers had ocular defects, with9of them got an ectopia lentis.Genotype-phenotype analysis revealed that FBN1mutation carriers had higher involvement rates of cardiovascular and skeletal lesions when compared to ocular system (P=0.021of both compares). FBN1mutation carriers had a higher major cardiovascular lesion phenotype rate as compared to major ocular phenotype (70.0%VS.30.0%, P=0.004). Carriers of mutations located at the cysteine domain of the FBN1gene had a higher rate of developing ectopia lentis when compared to other domains (100.0%VS.19.2%, P=0.008). PTC mutation carriers had higher major cardiovascular lesion phenotypes than mutation carriers of other regions (92.9%VS.50.0%, P=0.017)Conclusion:These results extend the FBNl mutation spectrum of the Chinese population, and we detected30mutations, with26of them were previously unreported. Genotype-phenotype analysis revealed that FBN1mutation carriers had a higher involvement rate of cardiovascular and skeletal systems when compared to the ocular system. Cysteine domain mutation carriers are tending to develop ectopia lentis, while PTC mutation carriers are easier to got major cardiovascular lesions. Genetic information of MFS families can predict the phenotypes of FBN1mutation carriers; can monitor the onset and development of the MFS; it can also help in the prevention of MFS. Background:Transforming growth factor beta receptor Ⅱ gene (TGFBR2) mutations are associated with Marfan syndrome; however, the relationship between the mutations and clinical phenotypes are not clear.Methods:Genomic DNA from peripheral blood leukocytes of a Chinese proband with Marfan syndrome, five of the proband's relatives, and100unrelated Chinese control subjects were isolated and screened for fibrillin-1(FBN1) and TGFBR2gene mutations by direct sequencing, and a genotype-phenotype study was carried out following a review of the literature on TGFBR2mutations in the search area. Also, the structure of TGFBR2protein before and after gene mutation was analyzed.Results:The results identified a novel missense TGFBR2mutation p.V453E (c.1358T>A) in the proband and two relatives that were located in the F-helix in the kinase domain of TGFBR2. No such genetic change was observed in the unrelated controls. No FBN1mutation was detected in any of the subjects. Genotype-phenotype analyses indicated that F-helix mutations are related to type2Marfan syndrome and Loeys-Dietz syndrome, and these mutations can lead to severe cardiovascular (93.8%) and skeletal (81.3%) lesions and minor ocular lesions (25%).Conclusions:The findings extend the mutation spectrum of Marfan syndrome, and that mutations at the F-helix in the kinase domain of TGFBR2may be associated with the development of severe cardiovascular and skeletal lesions and minor ocular lesions. Background:Controversies exist among trials reporting the effects of statins on endothelial dysfunction in patients with diabetes mellitus (DM). Therefore, we performed a meta-analysis to determine whether statin therapy could improve endothelial dysfunction in patients with DM.Methods:PubMed, Cochrane and Embase were searched for randomized controlled trials of statins. Only trials reporting changes in flow-mediated dilatation (FMD) were included in this analysis. A meta-analysis was performed to assess the relationship between statin therapy and improvements in endothelial dysfunction. Meta-regression and subgroup analyses were done to identify sources of heterogeneity.Results:Ten statin studies (845patients) were included in this analysis. Statin therapy significantly improved FMD in patients with DM [weighted mean difference (WMD):0.94%;95%CI:0.38%,1.5%; P<0.001]. Although heterogeneity among trials was found (P:67%), no significant publication bias was detected. Subgroup analyses showed that patients did not benefit from statin therapy if their body mass index (BMI) was>27.6kg/m2(four trials; P:0%; WMD:0.11%;95%CI:-0.47%,0.70%; P=0.70). However, FMD was significantly improved among patients with BMI≤27.6kg/m2(five trials; P:14%; WMD:1.52%;95%CI:1.19%,1.85%; P<0.001). Type1diabetes, younger age, lower baseline blood lipid levels and blood pressure were all associated with improvements in FMD. The meta-regression analysis yielded similar results.Conclusion:Statins significantly improved the FMD only in patients with better endothelial functions. The use of FMD in evaluating therapeutic outcomes should be careful in populations at high risk.