Genetic determinants of lipid traits in type 2 diabetes mellitus

产品说明：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，并且已经确定了许多单基因血脂紊乱的遗传变异，但一般人群和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2型糖尿病家族中，我们发现高加索人染色体3p12.1-q13.31（LOD=3.36）和西班牙裔人染色体11p15.4-p11.3（LOD=2.45）上的甘油三酯与HDL比率存在连锁关系。在非裔美国人的19p13.2-q13.42上也发现了总胆固醇（LOD=2.26）的连锁证据。在至少三个独立的人群中，这些区域中的每一个都与血脂水平的控制有关。我们假设3p12.1-q13.31、11p15.4-p11.3和19p13.2-q13.42含有调节2型糖尿病个体脂质性状的基因。我们建议通过首先细化染色体3，11和19上的连锁区域来解决这一假设，这将缩小连锁区间并增加信息含量，然后对位于每个区域内的基因进行有针对性的表征，以确定脂质性状的变异。将检测从连锁研究中识别出的遗传变异与高加索人、西班牙裔和非洲裔美国人家族中血浆脂质浓度的相关性，并评估变异对连锁的影响。为了鉴定最强连锁区域中靶向基因方法可能遗漏的潜在脂质相关变体，将建立3号染色体连锁区间的基于基因的连锁不平衡图谱。研究与公共卫生的相关性：脂质水平受遗传因素控制。该建议的目的是通过鉴定与特定染色体区域相关的脂质相关基因座来促进我们对与2型糖尿病相关的脂质异常的理解。鉴定调节脂质水平的基因将增强我们对脂质相关性状遗传的理解，为发生心脏病风险最大的目标个体提供标记，并可能导致血脂异常治疗策略的改进。

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.