MULTIPLE SEVERE OBESITY RISK GENES IN UTAH PEDIGREES

犹他州家系中的多个严重肥胖风险基因

• 批准号: 7340178
• 负责人: Steven C. Hunt
• 金额: $ 32.22万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340178
• 关键词: 20q; Architecture; Biological; Chromosomes; Chromosomes, Human, Pair 20; Collaborations; Communities; Complex; Condition; Congenic Mice; Data; Disease; Family; Family member; Female; Gender; Gene Mutation; Genes; Genetic; Genetic Epistasis; Genome; Heterogeneity; Human; Investigation; Lead; Link; Location; Lod Score; Maps; Modeling; Morbid Obesity; Mutation; Obesity; Pathology; Patients; Penetrance; Phenotype; Polynesian; Population; Prevention; Publishing; Recruitment Activity; Relative (related person); Research Personnel; Sampling; Series; Statistical Models; Study Subject; Susceptibility Gene; Testing; Time; Utah; Validation; Weight maintenance regimen; base; case control; concept; conditioning; congenic; cost; disability; disorder risk; editorial; gene interaction; genetic pedigree; improved; moderate obesity; mortality; mouse model; obesity risk; programs; segregation; trait

DESCRIPTION (provided by applicant): Multiple Severe Obesity Risk Genes in Utah Pedigrees Severe obesity (BMIS35 kg/m2) comprises a special subset of obesity for which the risk of disease, disability, and mortality is extremely high. Severe obesity has a significant genetic component and current hypotheses suggest underlying genes for severe obesity have larger effects (or greater penetrance) than genes contributing to mild or moderate obesity. Improvements in statistical modeling have led to increased published evidence of genetic epistasis and gender-specific effects, supporting the long-held view that obesity is a complex disease involving multiple genes that interact in complex ways. Evidence is presented herein of a new susceptibility gene we have identified for severe obesity, TBC1D1, that clearly segregates in female family members with severe obesity and explains most of the >9 LOD score. The unique set of large Utah pedigrees with many very severely obese subjects led to such dramatic linkage evidence, followed by significant association and biological evidence. Furthermore, evidence is presented that another unlinked locus on chromosome 4q shows strong evidence of statistical interaction with TBC1D1, such that conditioning on TBC1D1 by analyzing only families segregating TBC1D1 increases the 4q LOD score from 1.7 to 5.0. Since the presence of TBC1D1 does not lead to severe obesity in all carriers, the above result suggests that other gene(s) are also necessary for full expression of obesity. We have also published evidence that a locus on chromosome 20 appears to contain two closely linked genes, one with a dominant and one with a recessive effect on severe obesity (LOD=4.9). This locus was placed in a congenic mouse line which also showed evidence for multiple obesity phenotypes. Further, when the chromosome 20 LOD scores from families segregating for TBC1D1 and the 4q locus were examined, there was additional overlap of some pedigrees. This further suggests that these pedigrees contain multiple genes acting together in unknown fashion resulting in the dense aggregation of severe obesity in these pedigrees. This application proposes to identify, through fine mapping and sequencing, the region 4q gene and chromosome 20 gene(s) to examine nonadditive and gender-specific effects of these genes. Because TBC1D1 has already been identified, this study has the advantage of conditioning on a known, common, susceptibility gene in order to find additional genes and model how they might lead to severe obesity. This highly informative set of pedigrees will be used to further unravel the complexity of the genetic underpinnings of severe obesity that may contribute to the understanding of less severe obesity. Validation will be tested in a large case/control series, Polynesian families, and, for chromosome 20, in the congenic mouse model.

描述（由申请人提供）：犹他州家系中的多种重度肥胖风险基因重度肥胖（BMIS 35 kg/m2）包括一种特殊的肥胖亚类，其疾病、残疾和死亡风险极高。严重肥胖具有重要的遗传成分，目前的假设表明，与导致轻度或中度肥胖的基因相比，导致严重肥胖的潜在基因具有更大的影响（或更大的突变率）。统计模型的改进导致了遗传上位性和性别特异性效应的发表证据增加，支持了长期以来的观点，即肥胖是一种复杂的疾病，涉及以复杂方式相互作用的多个基因。本文提供的证据表明，我们已经鉴定出一种新的严重肥胖症易感基因TBC 1D 1，其在患有严重肥胖症的女性家庭成员中明显分离，并解释了>9 LOD评分的大部分。犹他州的一组独特的大家系中有许多非常严重的肥胖受试者，导致了这种戏剧性的连锁证据，其次是显着的关联和生物学证据。此外，有证据表明，染色体4 q上的另一个非连锁位点显示出与TBC 1D 1的统计学相互作用的强有力证据，这样，通过仅分析分离TBC 1D 1的家族来调节TBC 1D 1，将4 q LOD得分从1.7增加到5.0。由于TBC 1D 1的存在并不导致所有携带者的严重肥胖，因此上述结果表明，其他基因也是肥胖症完全表达所必需的。我们还发表了20号染色体上的一个位点似乎包含两个紧密连锁的基因的证据，一个是显性的，另一个是隐性的，对严重肥胖有影响（LOD=4.9）。将该基因座置于同类小鼠品系中，该小鼠品系也显示出多种肥胖表型的证据。此外，当检查来自分离TBC 1D 1和4 q基因座的家庭的染色体20 LOD分数时，存在一些家系的额外重叠。这进一步表明，这些家系包含多个基因以未知的方式共同作用，导致这些家系中严重肥胖症的密集聚集。本申请提出通过精细定位和测序鉴定4 q区基因和20号染色体基因，以检查这些基因的非加性和性别特异性效应。由于TBC 1D 1已经被识别出来，因此这项研究的优势是以已知的、常见的易感基因为条件，以便找到其他基因并模拟它们如何导致严重肥胖。这套信息量很大的谱系将被用来进一步揭示严重肥胖症遗传基础的复杂性，这可能有助于理解不太严重的肥胖症。将在大型病例/对照系列、波利尼西亚家族和同源小鼠模型中对20号染色体进行验证。