Positional Candidate Genes Affecting Metabolic Syndrome

描述（由申请方提供）：腹部肥胖代谢综合征被认为是几种疾病的主要风险特征，包括具有重大经济成本的心血管疾病。在寻找这种综合征的遗传病因学，我们已经确定了3号染色体（3q27）上的数量性状位点（QTL）。该QTL已在几个种族群体中复制。本项目的目的是确定该QTL中两个新的位置基因APM 1和PR 0227在该综合征的病理生理学中的作用，我们检验了两个互补的假设。假设1指出，这两个基因的多态性可以影响该综合征的基本和精细表型的表达。为了检验这一假设，我们对这两个基因进行了全面的重测序，以确定25个同胞对中所有的多态性，这些同胞对被选择为QTL和肥胖和胰岛素抵抗不一致。然后在对观察到的QTL有贡献的家族的所有个体成员中测试鉴定的多态性。贝叶斯定量性状核分析方法用于确定与该综合征的基本和精细表型相关的那些功能多态性。这些多态性是否足以解释所观察到的QTL也进行了评估。假设2指出，APM 1和PRO 2207的多态性影响候选基因和协同共表达基因的靶组织mRNA水平。通过从25个不一致的同胞中获得脂肪和骨骼肌活检来检验这一假设，无论是基础的还是诱导稳态高胰岛素血症后的。定量微阵列和RT PCR程序用于确定靶组织中基因表达的动态。采用贝叶斯方法的转录组学搜索法，对25个同胞进行了代谢综合征发病机制的初步生物学通路的详细描述。已鉴定的APM 1和PRO227多态性、组织基因表达谱和生物学途径扰动之间的关联进行了评估。这一应用的优势取决于威斯康星州医学院人类生物学、迪肯大学分子遗传学和西南生物医学研究基金会遗传统计学专家组成的三方联盟。这些努力应该解开这种综合征的遗传基础的新知识。

DESCRIPTION (provided by applicant): The abdominal obesity metabolic syndrome is recognized as a major risk profile for several morbidities including cardiovascular disease with major economic cost. In search for the genetic etiology of this syndrome we have identified a quantitative trait locus (QTL) on Chromosome 3 (3q27). This QTL has been replicated across several racial groups. The objective of this project is to identify the role of two novel positional genes in this QTL, APM1 and PR0227, in the pathophysiology of this syndrome, we test for two complimentary hypotheses. Hypothesis 1 states that polymorphisms of these two genes could influence expression of basic and refined phenotypes of this syndrome. To test for this hypothesis we comprehensively resequence the two genes to identify all their polymorphisms in 25 sib pairs selected to be discordant for the QTL and for obesity and insulin resistance. Identified polymorphisms are then tested in all individual members of the families that contributed to observed QTL. The Bayesian Quantitative Trait Nucleartide Analysis method is utilized to determine those functional polymorphisms associated with the basic and refined phenotypes of this syndrome. Whether these polymorphyisms adequately account for the observed QTL is also evaluated. Hypothesis 2 states that polymorphisms in APM1 and PRO2207 influence target tissues mRNA levels of the candidate and cooperatively co-expressed genes. This hypothesis is tested by obtaining adipose and skeletal muscle biopsies from the 25 discordant sibs, both basely and after induction of steady state hyperinsulinemic enuglycemia. Quantitative microarray and rt PCR procedures are used to determine the dynamics of gene expression in the target tissues. The transcriptomic search modification of the Bayesian procedure method are used to identify influences of the candidate genes Detailed description of primary biologic pathways underlying the pathogenesis of the metabolic syndrome obtained in the 25 sibs. Associations between the identified APM1 and PRO227 polymorphisms, tissue gene expression profiles and perturbation in the biologic pathways is evaluated. The strength of this application rests upon the tri-consortium of experts in human biology at the Medical College of Wisconsin, in molecular genetics at Deakin University and in genetic statistics at Southwestern Foundation for Biomedical Research. These efforts should unravel novel knowledge into the genetic basis of this syndrome.