Structural Analysis Of Candidate Genes For Type 2 Diabetes and Obesity

2 型糖尿病和肥胖候选基因的结构分析

• 批准号: 8741550
• 负责人: Leslie J Baier
• 金额: $ 122.25万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8741550
• 关键词: 20 year old; Adult; Age; Alleles; American Indians; Animal Model; Arizona; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Childhood; Chinese People; Communities; Diabetes Mellitus; Disease; Energy Metabolism; Exhibits; Frequencies; Functional disorder; Genes; Genetic; Genotype; Glucose; Growth; High Prevalence; Hour; Human; In Vitro; Incidence; Individual; Inherited; Insulin; Insulin Resistance; LEPR gene; Leptin; Measures; Mutation; Native Americans; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Parents; Pathway interactions; Physiological; Pima Indian; Population; Predisposition; Prevalence; Reporting; Risk; Rivers; Role; Sampling; Technology; Variant; base; case control; disorder risk; glucose production; insulin secretion; lipid metabolism; population based; respiratory; response

A gene is considered a candidate gene for obesity or type 2 diabetes in Pima Indians if 1) it has a known physiological function in a pathway relevant to type 2 diabetes/obesity or 2) it is associated with diabetes/obesity in another human population or in an animal model. In the past year we have directly sequenced and genotyped all detected variants in more than 50 physiologic candidate genes for associations with BMI or diabetes. Genotyping was performed in two large population based samples of individuals collected from the Gila River Indian Community. One of the investigated genes was KCNQ1. This gene was initially identified as a type 2 diabetes gene in a Chinese population, but it also appears to have a significant role in determining type 2 diabetes, obesity, and early insulin secretion response in Pima Indians. Variants in this gene exhibit parent of origin effects, such that the variants have different effects on disease risk if they were inherited maternally or paternally. Rare variants in genes along the Leptin/Melanocortin pathway cause severe monogenic obesity in childhood; therfore, genes along this pathway were also sequenced as candidate genes for obesity in Pima Indians.Sequenced genes include LEP, LEPR, POMC, MC4R,Sim1 and BDNF. Common variation in LEPR was identified that was reproducibly associated with modest changes in BMI, and the risk allele for overweight was associated with a decrease in energy expenditure measured over 24 hours in a human respiratory chamber. This is the first report of variation in LEPR effecting energy expenditure in humans. Many years ago we first sequenced MC4R in a small number of case/control samples for obesity and identified some missense variants. With the recent advances in sequencing technology, we have now been able to determine the frequency of functional mutations in MC4R in a population-based sample of American Indians who reside on the Gila River Indian Community, and analyze their effects on growth during childhood and adulthood.Sequencing of MC4R in 6760 Pima Indians identified 1 nonsense and 9 missense variants, of which 3 may be private to Pima Indians. We performed in vitro functional studies on each of these variants and found that 6 of the 10 caused decreased MC4R function. These 6 functional mutations occurred in 159 individuals (2.4% of the population). We found a greater rate of body mass accumulation and risk of type 2 diabetes before the age of 20 years in individuals with MC4R deficiency, but did not observe a difference in adulthood, indicating that the effects of these mutations are more apparent during the active growth of childhood.

如果1）在与2型糖尿病/肥胖症相关的途径中具有已知的生理功能，或2）在另一人群或动物模型中与糖尿病/肥胖症相关，则认为基因是皮马印第安人肥胖症或2型糖尿病的候选基因。在过去的一年中，我们直接测序和基因分型了50多个与BMI或糖尿病相关的生理候选基因中的所有检测到的变异。基因分型进行了两个大的人口为基础的样本从希拉河印第安社区收集的个人。其中一个被研究的基因是KCNQ 1。该基因最初在中国人群中被鉴定为2型糖尿病基因，但它似乎在决定Pima印第安人的2型糖尿病，肥胖和早期胰岛素分泌反应方面也具有重要作用。该基因的变异表现出亲本的起源效应，因此如果它们是母系或父系遗传的，则变异对疾病风险具有不同的影响。 Leptin/Melanocortin通路基因沿着的罕见变异导致儿童期严重的单基因肥胖;因此，Pima印第安人也将沿该通路的基因沿着作为肥胖的候选基因进行测序，测序的基因包括LEP、LEPR、POMC、MC 4 R、Sim 1和BDNF。LEPR的常见变异被鉴定为与BMI的适度变化可重复相关，并且超重的风险等位基因与在人类呼吸室中测量的24小时内的能量消耗减少相关。这是第一份关于LEPR变化影响人类能量消耗的报告。许多年前，我们首先对少数肥胖病例/对照样本中的MC 4 R进行了测序，并鉴定了一些错义变体。随着测序技术的最新进展，我们现在已经能够确定居住在吉拉河印第安社区的美国印第安人群体样本中MC 4 R功能突变的频率，并分析其对儿童和成年期生长的影响。 其中3个可能是皮马印第安人的私人财产。我们对每一种细胞进行了体外功能研究， 这些变体，并发现10个中的6个导致MC 4 R功能降低。这6个功能 突变发生在159个个体中（占群体的2.4%）。我们发现， 糖尿病患者在20岁之前的体重累积和2型糖尿病的风险 MC 4 R缺乏，但在成年期没有观察到差异，这表明 这些突变在儿童期的活跃生长期更为明显。