Candidate Genes Affecting Adolescent Metabolic Syndrome

描述(申请人提供)：肥胖及其相关的代谢综合征在美国青少年中达到流行状态，并有可能更早地出现共病，包括2型糖尿病和心血管疾病。我们的小组目前被资助以确定它们的生物前体的数量遗传学以及3q27 QTL候选位置基因的变异对其在177个高度信息量的家庭的成年成员中表达的影响。这项申请的具体目标是将他们青春期前、青春期和青春期后的后代包括在内。这一目标是通过三个互补的假设和具体目标来实现的。假设1：“青少年代谢综合征的生物前体和临床成分在遗传上是相互关联的。”在具体目标1中，确定了生物前体(全身脂肪和肌肉、腹部、内脏和皮下脂肪分布、胰岛素动力学和敏感性指数、低密度脂蛋白和高密度脂蛋白密度谱、循环中细胞因子/脂肪因子水平和内皮细胞过度活动/黏附标志物)与临床成分(体重指数、腰围和臀围、空腹血糖和胰岛素、血脂和脂蛋白、静息脉压和血压)的数量遗传学和相互关系。假设2：APM1、PSARL和新发现的位置基因ABCC5、HTR3E、KCNMB3、CCDC5和KIAA0804的多态性影响青少年代谢综合征的表达。在特定目标2中，对所有个体进行由全面重新测序的候选基因识别的所有多态的基因分型，并确定因果关联的多态。假设3：3q27位置候选基因表达的因果关联多态受青少年阶段和年龄的影响。在具体目标3中，根据青少年及其成年家庭成员的数据确定不同青少年阶段和不同年龄之间的相互作用。综合的结果应该提供对这种综合征及其共病的遗传起源的全球洞察。与机构使命的相关性：通过该项目获得的信息将有助于理解代谢综合征的遗传起源，目前代谢综合征被认为是2型糖尿病和心血管疾病的主要风险因素。这一知识应有助于开发新的预防手段和/或治疗方法。

DESCRIPTION (provided by applicant): Obesity and its associated metabolic syndrome attained epidemic status in U.S. adolescents with the potentiality of earlier onset of their co-morbidities, including type 2 diabetes and cardiovascular disease. Our group is currently funded to determine the quantitative genetics of their biologic precursors and the effects of the 3q27 QTL positional candidate gene's variances on its expression in the adult members of 177 our highly informative families. The specific objective of this application is to include their pre-, peri-, and post- adolescent descendents. This objective is pursued via three complementary hypotheses and specific aims. Hypothesis 1: "Biologic precursors and clinical components of the adolescent's metabolic syndrome are genetically intercorrelated." In Specific Aim 1, quantitative genetics and intercorrelations of the biologic precursors (total body fat and muscle, abdominal, visceral, and subcutaneous fat distribution, indices of insulin dynamics and sensitivity, LDL and HDL density profiles, circulating levels of cytokines/adipokines, and endothelial hyperactivity/adhesion markers) and the clinical components (BMI, waist and hip circumference, fasting plasma glucose and insulin, lipids and lipoproteins, and resting pulse and blood pressure) are determined. Hypothesis 2: "Polymorphisms in APM1, PSARL and the newly identified positional genes ABCC5, HTR3E, KCNMB3, CCDC5 and KIAA0804, influence expression of the adolescent's metabolic syndrome." In Specific Aim 2, all individuals are genotyped for all polymorphisms identified by comprehensively resequenced candidate genes and the causally associated polymorphisms are determined. Hypothesis 3: "Causally associated polymorphisms of the 3q27 positional candidate gene's expression are influenced by the adolescent's stage and age." In Specific Aim 3, the genotype- by-adolescent stage and -by-age interactions are determined from the adolescent's and their adult family member's data. The combined outcome should provide a global insight into the genetic origin of this syndrome and its co-morbidities. Relevancy to Agency's Mission: Information gained by this project will help contribute to understanding the genetic origins of the metabolic syndrome, now considered the major risk factor for type 2 diabetes and cardiovascular disease. This knowledge should assist in the development of new preventative means and/or therapies.