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(申请人提供)：代谢综合征(MS)描述胰岛素抵抗和代谢性心血管疾病危险因素的聚集。鉴于这种疾病造成了巨大的临床和公共卫生负担，进一步了解其遗传病因是重要的。最近在NHLBI家庭心脏研究中对MS的综合测量进行的基因组扫描发现，在2号染色体240 cM处存在显著的连锁(LOD3.34，p=0.00004)。这个为期3年的项目的总体目标是利用连锁不平衡(LD)定位来确定染色体2q35-2q37上的19.5Mb区域，以确定影响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。最初的精细定位将通过遗传病研究中心(CIDR)的支持进行，该中心已同意在来自FHS家系的1122名高加索受试者中对1536个SNP进行基因分型，这些SNP对连锁高峰有贡献。利用这些数据，将使用最先进的方法来模拟LD的模式并识别重组热点。基于家庭的方法将被用来测试个体SNPs和多位点单倍型与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被额外的SNP饱和，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。为了证实最令人信服的发现，将在FHS随机选择的无关高加索受试者(n=750)的独立样本中测试SNPs或单倍型与综合MS测量之间的关联。识别影响多发性硬化症的基因，不仅将进一步了解解释异常聚集性的病因途径，而且可能为筛查和预防提供新的策略。