Positional Candidate Genes Affecting Metabolic Syndrome

描述（由申请人提供）：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。为了寻找该综合征的遗传病因，我们在3号染色体（3q27）上发现了一个数量性状位点（QTL）。这个QTL已经在几个种族群体中得到了复制。该项目的目的是确定该QTL中两个新的定位基因APM1和PR0227在该综合征的病理生理中的作用，我们测试了两个互补的假设。假设1表明，这两个基因的多态性可能影响该综合征的基本表型和精致表型的表达。为了验证这一假设，我们对这两个基因进行了全面的重排序，以确定25对兄弟姐妹中选择的QTL和肥胖和胰岛素抵抗不一致的所有多态性。确定的多态性然后在所有促成观察到的QTL的家庭成员中进行测试。贝叶斯数量性状核潮分析方法用于确定与该综合征的基本表型和精制表型相关的功能多态性。这些多态性是否足以解释观察到的QTL也进行了评估。假设2认为APM1和PRO2207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。这一假设是通过从25个不一致的兄弟姐妹中获得脂肪和骨骼肌活检来验证的，无论是在基础上还是在诱导稳态高胰岛素性血糖后。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。使用贝叶斯程序方法的转录组学搜索修饰来确定候选基因的影响，详细描述了在25个兄弟姐妹中获得的代谢综合征发病机制的主要生物学途径。鉴定的APM1和PRO227多态性、组织基因表达谱和生物通路扰动之间的关系进行了评估。这项申请的力量取决于威斯康星医学院人类生物学专家、迪肯大学分子遗传学专家和西南生物医学研究基金会遗传统计学专家的三方联盟。这些努力将揭示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.