Identifying Susceptibility Genes for Metabolic Syndrome

鉴定代谢综合征的易感基因

• 批准号: 7564046
• 负责人: JAMES S PANKOW
• 金额: $ 35.72万
• 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 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564046
• 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; 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 Density Lipoproteins; Hip region structure; Hyperglycemia; Hypertension; 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; National Heart, Lung, and Blood Institute; Pathway interactions; Pattern; Phenotype; Plasminogen Activator Inhibitor 1; Predisposition; Prevalence; Prevention; Public Health; Reporting; Research; Research Personnel; Risk Factors; SNP genotyping; Sampling; 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危险因素的聚集。鉴于这种情况造成的巨大临床和公共卫生负担，进一步了解其遗传病因非常重要。最近，NHLBI 家庭心脏研究 (FHS) 中对 MS 的综合测量进行的基因组扫描发现，2 号染色体上 240 cM 处存在显着连锁（LOD=3.34，p=0.00004）。至少 19 项其他与 MS 相关表型的研究也涉及 2 号染色体的这一相同广泛区域。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 2q35-2q37 上 19.5 Mb 的区域，以识别影响 MS 易感性的基因。将使用多种策略来识别、表征和确认该区域的 MS 基因。最初的精细绘图将在遗传性疾病研究中心 (CIDR) 的支持下进行，该中心已同意对来自 FHS 谱系的 1122 名白人受试者中的 1536 个 SNP 进行基因分型，从而促成连锁峰。利用这些数据，最先进的方法将用于对 LD 模式进行建模并识别重组热点。基于家族的方法将用于测试个体 SNP 和多位点单倍型以及 MS 综合测量之间的关联。在初步结果的基础上，选定的区域和候选基因将充满额外的 SNP，以努力识别因果变异。可以对选定的候选基因进行重新测序，以充分探索这些基因座的遗传变异。为了确认最令人信服的发现，SNP 或单倍型与复合 MS 测量之间的关联将在来自 FHS 的随机选择的无关白人受试者 (n=750) 的独立样本中进行测试。鉴定影响多发性硬化症的基因不仅可以进一步了解解释异常聚集的病因途径，还可以提供新的筛查和预防策略。