Identifying Susceptibility Genes for Metabolic Syndrome

鉴定代谢综合征的易感基因

• 批准号: 7054429
• 负责人: JAMES S PANKOW
• 金额: $ 4.49万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7054429
• 关键词: cell line; clinical research; family genetics; genetic mapping; genetic markers; genetic susceptibility; human data; human genetic material tag; metabolic syndrome; quantitative trait loci; single nucleotide polymorphism

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 scans 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 14 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. Single nucleotide polymorphisms (SNPs) will be genotyped in 16 candidate genes prioritized by biological function (average density 1 per 10 kb) in 1122 subjects from the 150 FHS pedigrees contributing to the linkage peak. For regions outside these candidate genes, SNPs will be typed an average density 1 per 30 kb. 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. 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 subjects (n=750) from FHS. In addition, the effects of implicated SNPs on gene expression will be tested in lymphoblast cell lines, preadipocyte tissue, and brain samples. 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.

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。最近的基因组扫描了NHLBI家庭心脏研究（FHS）中MS的复合度量，发现在240 cm时2染色体上有显着的联系（LOD = 3.34，P = 0.00004）。至少有14项与MS相关的表型的研究与2号染色体的相同区域相同。这个三年项目的总体目标是使用使用19.5 MB区域的2q35-2q37染色体区域来表征 连锁不平衡（LD）映射以识别影响对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。单核苷酸多态性（SNP）将在16个由生物学功能（平均密度为1每10 kb的平均密度1）优先的16个受试者中的150名FHS谱系受试者中的16个候选基因中进行基因分型。对于这些候选基因以外的区域，SNP的平均密度为每30 kb的平均密度为1。最新的方法将用于建模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。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随机选择的无关受试者（n = 750）的独立样本中进行测试。此外，涉及SNP对基因表达的影响将在淋巴细胞细胞系，前脂肪细胞组织和脑样本中进行测试。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。