Genetics and Evolution of Fetal Human Fat Accretion During Development

胎儿发育过程中脂肪积累的遗传学和进化

基本信息

批准号：
8581302
负责人：
William L Lowe
金额：
$ 37.11万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8581302
关键词：
Accounting Address Adipose tissue Adult Affect American Architecture Asians Biology Birth Birth Weight Body fat Brain C-Peptide Cardiovascular system Caribbean region Childhood Chromosomes, Human, Pair 3 Complex DNA Data Data Collection Development Diabetes Mellitus Disease Energy-Generating Resources Enrollment European Evolution Exhibits Fatty acid glycerol esters Frequencies Functional RNA Funding Gene Expression Genetic Genetic Research Genetic Variation Genomics Genotype Glucose Goals Growth Health Heart Human Human Genetics Human Resources Hyperglycemia Laboratories Life Mammals Measures Metabolic Mexican Americans Morbidity - disease rate Mothers Neonatal Newborn Infant Obesity Observational Study Outcome Outcome Study Phenotype Predisposition Pregnancy Pregnancy Outcome Primates Protocols documentation Race Resources Risk Role Serum Sum Testing Third Pregnancy Trimester Tissues Training Triglycerides United States National Institutes of Health Untranslated RNA Variant Woman cohort comparative genomics disease phenotype disorder risk fetal functional genomics genetic evolution genetic variant genome wide association study glucose tolerance human data insight instrument next generation sequencing nonhuman primate offspring public health relevance subcutaneous trait

项目摘要

DESCRIPTION (provided by applicant): Newborns with high or low body fat at birth have an increased susceptibility to poor metabolic and/or cardiovascular health in childhood and adulthood. Unlike adult adiposity which is present in essentially all mammals, significant fat mass at birth is unique to humans among primates and mammals more generally, suggesting a recently evolved genetic component. Fat accretion during development is modulated by maternal metabolic factors (e.g., glucose and triglycerides), but we have now determined that genetic factors also contribute to newborn human adiposity at birth. In a genome wide association study performed in a multi-ethnic cohort of newborns whose mothers underwent glucose testing during gestation we identified a locus on chromosome 3, 3q25.31, which exhibits association in multiple race groups with measures of newborn adiposity. The associated region is intergenic, and we are proposing to identify genetic variation within the locus to address the hypothesis that genetic variants within 3q25.31 affect the expression of long noncoding RNAs present in the locus. We will address this hypothesis by performing the following specific aims using DNA and phenotype data collected as part of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study. Aim 1: To use targeted genomic capture and next generation sequencing to identify additional common, low frequency and rare variants within 3q25.31 in a total of 800 newborns of Northern European, Afro-Caribbean, Mexican-American and Thai ancestry in the upper and lower 10th percentiles for sum of skinfolds, a measure newborn adiposity. Aim 2: To use high throughput approaches to define the impact of variants on gene expression and expression of lncRNAs within the chromosome 3 locus. Aim 3: To use comparative genomic approaches to define the underlying genetic architecture and function of the chromosome 3 locus in humans compared to other non-human primates. Aim 4: To demonstrate that variants which have a functional impact are associated with measures of newborn adiposity by genotyping the identified SNPs in up to 10,900 additional HAPO newborns from the four race groups. Accomplishing these aims will provide fundamental new insight into genetic factors regulating newborn anthropometric traits. This will have important implications for fetal outcomes, long-term health of the newborn, and evolution of unique human traits important for the support of neonatal brain growth.

描述（由申请人提供）：出生时脂肪高或低体内脂肪的新生儿对儿童和成年期的代谢和/或心血管健康的敏感性增加。与所有哺乳动物本质上存在的成人肥胖不同，出生时大量的脂肪质量是人类在灵长类动物和哺乳动物中更普遍的独有的，这表明最近进化的遗传成分。发育过程中的脂肪吸收受母体代谢因子（例如葡萄糖和甘油三酸酯）的调节，但我们现在确定遗传因素在出生时也有助于新生的人类肥胖。在一项多种族的新生儿队中进行的一项基因组宽结合研究中，他的母亲在妊娠期间接受了葡萄糖测试，我们确定了3q25.31染色体上的一个基因座，该基因座在多个种族组中与新生儿肥胖的测量表现出了关联。相关区域是基因间的，我们建议识别基因座中的遗传变异，以解决以下假设：3Q25.31之内的遗传变异会影响基因座中存在的长未编码RNA的表达。我们将通过使用DNA和表型数据作为高血糖和不良妊娠结局（HAPO）研究的DNA和表型数据进行以下特定目标（HAPO）研究来解决这一假设。目的1：使用有针对性的基因组捕获和下一代测序，以在3q25.31范围内识别出其他共同的，低频和稀有的变体，共有800名北欧新生儿，北欧新生儿，非洲 - 加勒比海，墨西哥裔美国人和泰国祖先在上层和下10个百分位数中，用于skinfolds的超级和新生儿脂肪的总和。 AIM 2：使用高吞吐量方法来定义变体对3染色体基因座中LNCRNA的基因表达和表达的影响。目标3：使用比较基因组方法来定义与其他非人类灵长类动物相比，人类3染色体3基因座的基本遗传结构和功能。 AIM 4：证明具有功能影响的变体通过基因分型在四个种族组中的多达10,900个HAPO新生儿中的鉴定SNP进行基因分型，与新生儿肥胖的度量有关。实现这些目标将为调节新生儿人体测量特征的遗传因素提供基本的新见解。这将对胎儿结局，新生儿的长期健康以及对支持新生儿大脑生长至关重要的独特人类特征的演变具有重要意义。