Identifying Susceptibility Genes for Metabolic Syndrome

鉴定代谢综合征的易感基因

基本信息

批准号：
7209587
负责人：
JAMES S PANKOW
金额：
$ 37.41万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-29 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7209587
关键词：
2q35 2q35-q37 2q37 Accounting Adult Affect Amino Acids Arts Biological Neural Networks Biological Process Body mass index Candidate Disease Gene Carbohydrates Cardiovascular Diseases Caucasians Caucasoid Race Central obesity Cholesterol Chromosome Mapping Chromosomes Chromosomes, Human, Pair 2 Clinical Collaborations Condition Custom DNA Resequencing Data Databases Disease Education Environment Exhibits Family Family Study Fasting Fatty Acids Gene Combinations Gene Frequency Genes Genetic Predisposition to Disease Genetic Recombination Genetic Variation Genome Scan Genomics Genotype Goals HDL-triglyceride Haplotypes Heart High Blood Pressure High Density Lipoproteins Hip region structure Hyperglycemia Hypertriglyceridemia Individual Inherited Insulin Resistance Joints Laboratories Laboratory Finding Linkage Disequilibrium Linkage Disequilibrium Mapping Lipids Literature Maps Measures Metabolic Metabolic syndrome Metabolism Methods Minor Modeling Molecular Genetics Pathway interactions Pattern Phenotype Plasminogen Activator Inhibitor 1 Predisposition Prevalence Prevention Public Health Reporting Research Research Personnel Risk Factors SNP genotyping Sampling Score Screening procedure Services Single Nucleotide Polymorphism Map Statistical Methods Structure Susceptibility Gene Testing Uric Acid Utah Variant base blood glucose regulation combinatorial density genetic epidemiology genetic linkage analysis genetic pedigree genome wide association study novel novel strategies programs research facility steroid metabolism

项目摘要

DESCRIPTION (provided by applicant): The metabolic syndrome (MS) describes the clustering of insulin resistance and metabolic CVD risk factors. Given the substantial clinical and public health burden imposed by this condition, further understanding of its genetic etiology is important. A recent genome scan for a composite measure of the MS in the NHLBI Family Heart Study (FHS) found significant linkage on chromosome 2 at 240 cM (LOD=3.34, p=0.00004). This same broad region of chromosome 2 has been implicated by at least 19 other studies for phenotypes related to the MS. The overall goal of this 3-year project is to characterize a 19.5 Mb region on chromosome 2q35-2q37 using linkage disequilibrium (LD) mapping to identify genes influencing susceptibility to the MS. Multiple strategies will be used to identify, characterize, and confirm MS genes in this region. Initial fine mapping will be conducted through support from the Center for Inherited Disease Research (CIDR), which has agreed to genotype 1536 SNPs in 1122 Caucasian subjects from FHS pedigrees contributing to the linkage peak. Using these data, state-of-the-art methods will be used to model patterns of LD and identify recombination hotspots. Family-based methods will be used to test associations between individual SNPs and multilocus haplotypes and the MS composite measure. Building on initial results, selected regions and candidate genes will be saturated with additional SNPs in an effort to identify causal variants. Resequencing of selected candidate genes may be conducted to fully explore the genetic variation at those loci. To confirm the most compelling findings, associations between SNPs or haplotypes and the composite MS measure will be tested in an independent sample of randomly selected unrelated Caucasian subjects (n=750) from FHS. Identification of genes influencing the MS will not only further the understanding of etiologic pathways that explain the clustering of abnormalities, but also may offer novel strategies for screening and prevention.

描述（由申请人提供）：代谢综合征（MS）描述了胰岛素抵抗和代谢CVD风险因素的聚类。鉴于这种情况造成了实质性的临床和公共卫生负担，因此对其遗传病因的进一步了解很重要。 NHLBI家族心脏研究（FHS）中MS的复合度量的最新基因组扫描发现，在240 cm时2染色体上有显着连接（LOD = 3.34，P = 0.00004）。至少有19项与MS相关的表型的研究与2个染色体2的相同广泛区域有关。这个三年项目的总体目标是使用连锁不平衡（LD）映射在染色体2q35-2q37上表征19.5 MB区域，以识别影响对MS敏感的基因。将使用多种策略来识别，表征和确认该区域中的MS基因。最初的精细映射将通过遗传性疾病研究中心（CIDR）的支持进行，该研究已同意来自FHS谱系的1122名高加索受试者的基因型1536 SNP，从而促进了连锁峰。使用这些数据，最先进的方法将用于建模LD的模式并识别重组热点。基于家庭的方法将用于测试单个SNP和多焦点单倍型与MS复合度量之间的关联。在初始结果的基础上，选定的区域和候选基因将被其他SNP饱和，以识别因果变体。可以对选定的候选基因进行重新取证，以充分探索这些基因座的遗传变异。为了确认最引人注目的发现，SNP或单倍型与复合MS度量之间的关联将在FHS的随机选择无关的高加索受试者（n = 750）的独立样本中进行测试。影响MS的基因的鉴定不仅会进一步了解解释异常聚类的病因学途径，而且还可能为筛查和预防提供新颖的策略。