Identifying Susceptibility Genes for Metabolic Syndrome

鉴定代谢综合征的易感基因

• 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
• 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

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性CVD风险因素的聚集。鉴于这种情况造成的重大临床和公共卫生负担，进一步了解其遗传病因是重要的。在NHLBI家族心脏研究（FHS）中，最近对MS的综合测量进行的基因组扫描发现在240 cM处的2号染色体上存在显著连锁（LOD=3.34，p=0.00004）。至少有19项其他研究涉及到与MS相关的表型的2号染色体的这一相同的广泛区域。这个为期3年的项目的总体目标是使用连锁不平衡（LD）作图来表征染色体2 q35 - 2 q37上的19.5 Mb区域，以鉴定影响MS易感性的基因。并确认该区域的MS基因。最初的精细定位将在遗传疾病研究中心（CIDR）的支持下进行，该中心已同意对来自FHS家系的1122名高加索受试者中的1536个SNP进行基因型分析，这些受试者对连锁峰有贡献。使用这些数据，国家的最先进的方法将被用来模拟模式的LD和确定重组热点。将使用基于家族的方法来测试个体SNP和多位点单倍型与MS复合测量之间的关联。在初步结果的基础上，选定的区域和候选基因将被额外的SNP饱和，以识别致病变异。可以进行所选候选基因的重测序以充分探索那些基因座处的遗传变异。为了证实最令人信服的发现，SNPs或单倍型与复合MS测量之间的关联将在从FHS随机选择的无关白人受试者（n=750）的独立样本中进行测试。鉴定影响MS的基因不仅将进一步理解解释异常聚集的病因学途径，而且还可能提供筛查和预防的新策略。