Positional Candidate Genes Affecting Metabolic Syndrome

描述(由申请人提供)：腹型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。为了寻找这种综合征的遗传病因，我们在染色体3(3q27)上定位了一个数量性状基因座(QTL)。这个QTL已经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APM1和PR0227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说。假设1指出，这两个基因的多态可能会影响这种综合征的基本和精细表型的表达。为了验证这一假设，我们对这两个基因进行了全面的重新测序，以确定它们在25对同胞中的所有多态性，这些兄弟姐妹对被选为与QTL、肥胖和胰岛素抵抗不一致的。然后在对观察到的QTL有贡献的家庭的所有个体成员中进行识别的多态性测试。使用贝叶斯数量性状核糖核酸分析方法来确定与该综合征的基本表型和精炼表型相关的功能多态。还评估了这些多态是否充分解释了观察到的QTL。假设2指出，APM1和PRO2207基因的多态影响候选基因和协同表达基因的靶组织mRNA水平。这一假说是通过从25个不协调的同胞中获得脂肪和骨骼肌活检来检验的，这两种情况都是在基础上和诱导出稳定的高胰岛素血症后进行的。定量微阵列和RT-PCR程序被用来确定目标组织中基因表达的动态。对贝叶斯程序方法的转录搜索修改被用来确定候选基因的影响，详细描述了在25个同胞中获得的代谢综合征发病机制的主要生物学途径。对识别的APM1和PRO227多态、组织基因表达谱和生物通路中的扰动之间的关系进行了评估。这项申请的优势在于威斯康星医学院的人类生物学专家、迪肯大学的分子遗传学专家和西南生物医学研究基金会的遗传统计学专家组成的三个联盟。这些努力应该会揭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.