The Role of Mitochondrial Genes in Hypertension

线粒体基因在高血压中的作用

• 批准号: 7478413
• 负责人: FAINA SCHWARTZ
• 金额: $ 23.04万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7478413
• 关键词: Affect; African American; Alanine-Specific tRNA; Algorithms; Alleles; Biological; Biological Assay; Blood Pressure; Boston; Case-Control Studies; Caucasians; Caucasoid Race; Class; Clinic; Clinical; Complex; Computer Assisted; Data; Data Set; Databases; Defect; Detection; Discrimination; Disease; Family; Framingham Heart Study; Funding; Genes; Genetic; Genetic Polymorphism; Genotype; Haplogroup; Heritability; Hypertension; Individual; Medical center; Methods; Mitochondria; Mitochondrial DNA; Molecular; Mutation; Numbers; Parents; Participant; Phenotype; Phylogenetic Analysis; Recruitment Activity; Relative (related person); Reporting; Research Design; Role; Sampling; Sequence Analysis; System; Testing; Variant; blood pressure regulation; case control; clinical research site; cohort; genetic pedigree; member; mitochondrial DNA mutation; mitochondrial genome; normotensive; novel; proband; programs; trait

DESCRIPTION (provided by applicant): This competitive renewal application will further challenge our hypothesis that mitochondrial (mtDNA) defects are important contributors to hypertension (HTN). During the present funding period, we developed a novel method for the detection of mitochondrial involvement in complex disorders and applied it to the hypertension data set from 350 Caucasian and 98 African American pedigrees ascertained through the HTN clinics at Boston Medical Center and collaborating clinical sites. Remarkably, we found the fraction of families potentially due to mtDNA mutations to be approximately 55% (95% Cl, 45%-65%). Sequence analysis of the entire mitochondrial genome in 10 African American and 10 Caucasian hypertensive probands from families with suspected mitochondrial involvement led to the identification of several novel, as well as previously reported, mutations with a likely pathogenic effect. Molecular biological characterization of two mutations, T3308C in the ND1 gene and T5655C in the tRNA-Ala gene, detected in African Americans of Lib haplogroup, revealed a reduced Complex I activity in the mitochondrial cybrids containing these mutations. Preliminary data from case-control association study of another mutation, the A10398G in the ND3 gene, conducted in 700 unrelated individuals provided evidence for association of the 10398G allele with HTN. In the present application, we seek to confirm our findings in an independent cohort and to further assess the role of mtDNA variants in blood pressure (BP) homeostasis. Our specific aims are: 1) confirm maternal effect on BP inheritance in Framingham Heart Study participants using existing clinical and genetic data sets from 330 largest Framingham families; 2) identify rare mtDNA variants with potential effects on BP by sequencing the mitochondrial genome from individuals with extreme systolic (n=50) and diastolic (n=50) BP phenotypes; 3) test the association of selected mtDNA variants with HTN and related BP phenotypes by case-control and quantitative association analyses.

描述（由申请人提供）：这种竞争性更新应用将进一步挑战我们的假设，即线粒体（mtDNA）缺陷是高血压（HTN）的重要促进者。在目前的资金期间，我们开发了一种新的方法，用于检测复杂疾病中的线粒体参与，并将其应用于通过波士顿医疗中心和协作临床场所的HTN诊所确定的350名高加索人和98个非裔美国人的高血压数据集。值得注意的是，我们发现由于mtDNA突变的含量约为55％（95％Cl，45％-65％）。对10个非裔美国人的整个线粒体基因组和来自具有可疑线粒体受累家族的10个高加索高血压概率的序列分析，导致了几种新颖的鉴定，以及先前报道的突变，可能具有致病作用。在LIB Haplogroup的非裔美国人中检测到的两个突变，ND1基因中T3308C的分子生物学表征，T3308C和T5655C的分子生物学表征，揭示了含有这些突变的线粒体cybrid中的复合物I活性降低。病例对照关联研究另一个突变的初步数据，ND3基因中的A10398G，在700个不相关个体中进行了10398G等位基因与HTN的关联的证据。在本应用中，我们试图在独立队列中确认我们的发现，并进一步评估mtDNA变体在血压（BP）稳态中的作用。我们的具体目的是：1）使用现有的330个最大弗雷明汉家庭的现有临床和遗传数据集确认弗雷明汉心脏研究参与者中对BP遗传的影响； 2）通过对具有极端收缩期（n = 50）和舒张压（n = 50）BP表型的个体的线粒体基因组进行测序，通过对线粒体基因组进行测序，从而确定对BP的潜在影响的稀有mtDNA变体； 3）通过病例对照和定量关联分析测试选定的mtDNA变体与HTN和相关BP表型的关联。