Genetic determinants of lipid traits in type 2 diabetes mellitus

2型糖尿病血脂特征的遗传决定因素

• 批准号: 7072960
• 负责人: Johanna K DiStefano
• 金额: $ 42.75万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7072960
• 关键词: African American; Hispanic Americans; biotechnology; caucasian American; clinical research; diabetes mellitus genetics; family genetics; genetic markers; genetic screening; genetic susceptibility; genotype; human data; human genetic material tag; human tissue; hyperlipidemia; linkage disequilibriums; linkage mapping; lipid metabolism; molecular biology information system; noninsulin dependent diabetes mellitus; nucleic acid repetitive sequence; racial /ethnic difference; single nucleotide polymorphism

DESCRIPTION: Coronary heart disease, arising mainly from dysregulated lipid metabolism, is the leading cause of death among individuals with type 2 diabetes mellitus. Although lipid levels are strongly dependent upon genetic factors, and numerous genetic variants underlying monogenic lipid disorders have been identified, genetic determinants of lipid levels in both the general population and in individuals with type 2 diabetes remain unknown. In families ascertained for type 2 diabetes who participated in the American Diabetes Association- sponsored Genetics of Non-Insulin Dependent Diabetes (GENNID) study, we have found evidence of linkage for triglyceride-to-HDL ratio on chromosome 3p12.1-q13.31 (LOD=3.36) in Caucasians and 11p15.4-p11.3 (LOD=2.45) in Hispanics. Evidence for linkage was also found on 19p13.2-q 13.42 for total cholesterol (LOD=2.26) in African Americans. Each of these regions has been implicated in the control of lipid levels in at least three independent populations. We hypothesize that 3p12.1-q13.31, 11p15.4-p11.3, and 19p13.2- q 13.42 harbor genes which modulate lipid traits in individuals with type 2 diabetes. We propose to address this hypothesis by first refining the regions of linkage on chromosomes 3, 11, and 19, which will narrow the linkage interval and increase information content, followed by a targeted characterization of genes located within each region to identify variants that underlie lipid traits. The genetic variants identified will be tested for association with plasma lipid concentrations in Caucasian, Hispanic, and African American families from the linkage study and variant effects on linkage will be assessed. To identify potential lipid-related variants that might be missed in a targeted gene approach in the region of strongest linkage, a gene-based linkage disequilibrium map of the chromosome 3 linked intervals will be established. Relevance of research to public health: Lipid levels are under the control of genetic factors. The goal of this proposal is to advance our understanding of lipid abnormalities associated with type 2 diabetes mellitus through identification of lipid-related loci which have been linked to specific chromosomal regions. Identification of genes that regulate lipid levels will enhance our understanding of the inheritance of lipid- related traits, provide markers to target individuals at greatest risk for developing heart disease, and potentially lead to improved treatment strategies for dyslipidemia.

描述：冠心病主要由脂质代谢失调引起，是 2 型糖尿病患者死亡的主要原因。尽管血脂水平强烈依赖于遗传因素，并且已鉴定出单基因血脂紊乱背后的许多遗传变异，但普通人群和 2 型糖尿病患者中血脂水平的遗传决定因素仍然未知。在参与美国糖尿病协会赞助的非胰岛素依赖型糖尿病遗传学 (GENNID) 研究的确定患有 2 型糖尿病的家庭中，我们发现了染色体 3p12.1-q13.31 上甘油三酯与 HDL 比率关联的证据(LOD=3.36) 在白种人中，11p15.4-p11.3 (LOD=2.45) 在西班牙裔。在非裔美国人的总胆固醇 (LOD=2.26) 的 19p13.2-q 13.42 上也发现了关联的证据。这些区域中的每一个都与至少三个独立人群的脂质水平的控制有关。我们假设 3p12.1-q13.31、11p15.4-p11.3 和 19p13.2-q 13.42 含有调节 2 型糖尿病个体脂质特征的基因。我们建议通过首先细化 3、11 和 19 号染色体上的连锁区域来解决这一假设，这将缩小连锁间隔并增加信息内容，然后对位于每个区域内的基因进行有针对性的表征，以识别脂质基础的变异特征。将测试从连锁研究中确定的遗传变异与白种人、西班牙裔和非裔美国人家庭血浆脂质浓度的关联，并评估变异对连锁的影响。为了识别在最强连锁区域的靶向基因方法中可能遗漏的潜在脂质相关变异，将建立基于基因的 3 号染色体连锁间隔的连锁不平衡图。研究与公共卫生的相关性：脂质水平受遗传因素控制。该提案的目标是通过鉴定与特定染色体区域相关的脂质相关位点，增进我们对与 2 型糖尿病相关的脂质异常的理解。鉴定调节血脂水平的基因将增强我们对血脂相关性状遗传的理解，为罹患心脏病风险最大的个体提供标记，并有可能改善血脂异常的治疗策略。