Genetics of Metabolic Syndrome in an Island Population

描述（由申请人提供）：代谢综合征（MetS）是与心血管疾病和2型糖尿病发展相关的一系列危险因素，在西方工业化国家已达到流行病的程度。大约有4700万美国人患有MetS。因此，它对公共卫生产生了巨大影响。代谢综合征的标志是肥胖、血脂异常、碳水化合物不耐受和高血压的共同发生。个体组分和复合MetS性状的家族聚集表明遗传因素的参与。然而，我们对代谢综合征相关遗传因素的了解在很大程度上仍然不完整。 我们建议在克罗地亚亚得里亚海东部海岸赫瓦尔岛的一个孤立的人群中进行一项关于MetS流行病学和遗传学的彻底调查。隔离人群在复杂疾病基因定位中的价值已被广泛记录。研究人群MetS患病率高，在种族上与一般美国人群相关，其独特的进化史是由少数斯拉夫创始人建立的，地理隔离，环境同质性，大家庭规模为了解MetS遗传学提供了独特的机会。 我们建议：（1）从赫瓦尔省的5个村庄招募1200名20岁以上的个体，收集人口统计学、环境、生活方式、表型、相关临床数据和血液样本，用于生化性状和DNA分析;（2）进行适当的分析，以估计遗传贡献对MetS作为复合性状及其组成表型的变异性的影响;（3）使用一组密集间隔的10 K SNP标记进行全基因组扫描以进行连锁分析;（4）随后在显著连锁的区域中使用“位置候选”方法进行基于谱系的关联研究以鉴定与MetS相关的遗传变体。 这项研究具有巨大的公共卫生重要性，其科学价值是巨大的，有可能了解MetS的遗传病因。我们将研究一个理想的人群进行这项研究;我们使用密集的SNP标记的连锁和关联是一个国家的最先进的方法，并有巨大的承诺，为确定基因座和基因变异的基础MetS。

DESCRIPTION (provided by applicant): Metabolic syndrome (MetS), a constellation of risk factors associated with development of cardiovascular disease and Type 2 diabetes, has reached epidemic proportions in western industrialized nations. About 47 million Americans have MetS. Consequently, it has enormous impact on public health. The hallmark of MetS is a co-occurrence of obesity, dyslipidemia, carbohydrate intolerance and high blood pressure. Familial aggregation of the individual components and the composite MetS trait suggests involvement of genetic factors. However, our knowledge concerning the genetic factors underlying MetS remains largely incomplete. We propose to undertake a thorough investigation on epidemiology and genetics of MetS in an isolated population from the island of Hvar in the eastern Adriatic coast of Croatia. The value of isolated population in complex disease gene mapping has been widely documented. The study population has a high prevalence of MetS, is ethnically relevant to the general US population, with its distinct evolutionary history of recent founding by small number of Slavic founders, geographic isolation, environmental homogeneity, extended family sizes provides a unique opportunity to understand the genetics of MetS. We propose to (1) recruit 1200 individuals above 20 years of age from five villages of Hvar, collect demographic, environmental, life-style, phenotypic, relevant clinical data, and blood samples for analysis of biochemical traits and DNA; (2) conduct appropriate analyses to estimate the effects of genetic contribution to the variability of MetS as a composite trait and its constituent phenotypes; (3) conduct a whole genome scan using a panel of densely spaced, 10K, SNP markers for linkage analysis; (4) followed by pedigree-based association studies using a 'positional candidate' approach in the regions of significant linkage for identification of genetic variants associated with MetS. The study has enormous public health importance and its scientific merit is substantial with the potential of understanding the genetic etiology of MetS. We will study an ideal population for this research; our use of dense SNP markers for linkage and association is a state-of-the-art approach and has enormous promise for identifying loci and gene variants underlying MetS.