MOLECULAR GENETIC ANALYSIS OF HUMAN OBESITY

人类肥胖的分子遗传学分析

• 批准号: 2444177
• 负责人: RUDOLPH L LEIBEL
• 金额: $ 72.88万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-15 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2444177
• 关键词: African American; Hispanic Americans; Native Americans; South America; South American; United States; adipose tissue; alleles; body composition; body physical activity; body weight; caucasian American; cell bank /registry; genotype; human population genetics; human subject; linkage mapping; lymphocyte; mass screening; molecular genetics; obesity; phenotype; polymerase chain reaction; restriction fragment length polymorphism; southern blotting; tissue /cell culture

Obesity is among the most prevalent nutritional disorders in industrial societies. Approximately 27% of 6-11 year old and 21% of 12-17 year old individuals in the United States are currently obese, and 30-40% of obese adults were obese adolescents. Thirty four million adult Americans are obese. Obesity in adults accounts for over 80% of type II diabetes mellitus, and a substantial fraction of hypertension and disorders of lipid metabolism. Relative distribution of fat (abdominal:pelvic ratio) also plays a role in obesity-related morbidity/mortality. As much as 80% of the risk of obesity and a significant component of distribution of body fat may be due to genetic factors. None of these genetic factors has been identified. In mice, clear examples of Mendelian genetic transmission of obesity have been described and mapped to specific chromosome regions. Many aspects of the phenotype of these animals - most notably excess food intake and high metabolic efficiency - are similar to those encountered in obese humans. In humans, the Prader-Labhart-Willi syndrome (PW) is associated with extreme obesity of early onset. The high homology between relevant portions of the mouse and human genomes, makes it plausible that one or more allelic variants of the human homologues of these mouse genes contributes to obesity in man. We propose to examine human pedigrees in which obesity (as measured by body mass index) is segregating, for linkage to RFLP's from regions of the human genome syntenic with regions of the mouse genome where 5 obesity genes have been mapped, and to RFLP's from 15qll-13 where the P-W locus has been mapped. Measurements of abdominal and hip circumference will also be obtained in these pedigrees. 100 families (1100 individuals) will be characterized from both relatively inbred populations ( e.g. Pima Indians of Arizona; residents of Maracaibo, Venezuela), as well as from families with obesity in urban centers in the USA. Both child and adult probands will be used to identify families segregating an obese phenotype. Lymphoblastoid cell lines will be prepared on members of these pedigrees, creating a genetic resource in perpetuity. Tests for allelic association (linkage disequilibrium) affected sib-pair and genetic linkage analysis will be performed. Ultimately, this genetic resource can also be used to search for loci linked to specific aspects of phenotype using linked clones spanning the genome.

肥胖是工业中最普遍的营养障碍之一 社会。大约6-11岁的27％和12-17岁的21％ 美国的个人目前肥胖，肥胖的30-40％ 成人是肥胖的青少年。 30000万成年美国人是 肥胖。 成人的肥胖症占II型糖尿病的80％以上 Mellitus，以及大量的高血压和疾病 脂质代谢。 脂肪的相对分布（腹部：骨盆比） 还在与肥胖相关的发病率/死亡率中起作用。 多达80％ 肥胖风险和分布的重要组成部分 体内脂肪可能是由于遗传因素引起的。这些遗传因素都没有 已确定。 在小鼠中，明确的孟德尔遗传例子 肥胖的传播已被描述并映射到特定 染色体区域。 这些动物表型的许多方面 - 最值得注意的是，食物摄入过多和代谢效率高 - 是 与肥胖人类遇到的人相似。 在人类中 Prader-Labhart-Willi综合征（PW）与极端肥胖有关 早发。 鼠标相关部分之间的高同源性 和人类基因组，使一个或多个等位基因变体合理 这些小鼠基因的人类同源物有助于肥胖 男人。 我们建议检查肥胖症的人类血统（如测量 由体重指数）正在分离，以与RFLP的联系。 人类基因组与小鼠基因组区域的同步5 肥胖基因已被映射，并从13 Qll-13的RFLP映射到p-w。 基因座已被映射。 腹部和臀部周长的测量 也将在这些血统中获得。 100个家庭（1100个人） 将以相对近交的人群为特征（例如PIMA 亚利桑那州印第安人； Maracaibo，委内瑞拉）以及 在美国城市中心有肥胖的家庭。 儿童和成人 检验将用于识别隔离肥胖的家庭 表型。 淋巴母细胞细胞系将在 这些谱系，在永久性中创造了遗传资源。 测试 等位基因协会（连锁不平衡）影响了SIB-PAIR和 将进行遗传连锁分析。 最终，这种遗传 资源也可以用于搜索链接到特定方面的基因座 使用跨基因组的链接克隆的表型。