Genetic determinants of lipid traits in type 2 diabetes mellitus

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。尽管脂质水平在很大程度上依赖于遗传因素，并且已经发现了许多导致单基因脂质紊乱的遗传变异，但在普通人群和2型糖尿病患者中，脂质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型糖尿病家庭中，我们发现了白种人染色体3p12.1-q13.31 （LOD=3.36）和西班牙裔染色体11p15.4-p11.3 （LOD=2.45）上甘油三酯与高密度脂蛋白比值相关的证据。非裔美国人总胆固醇（LOD=2.26）的19p13.2-q为13.42，也发现了相关证据。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型糖尿病患者脂质特征的基因。为了解决这一假设，我们建议首先细化染色体3、11和19上的连锁区域，这将缩小连锁间隔并增加信息含量，然后对位于每个区域内的基因进行有针对性的表征，以确定构成脂质性状的变异。从连锁研究中，将检测鉴定出的遗传变异与白种人、西班牙裔和非裔美国家庭的血脂浓度的关系，并评估变异对连锁的影响。为了确定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3号染色体连锁间隔的基于基因的连锁不平衡图谱。研究与公众健康的相关性：脂质水平受遗传因素控制。本提案的目的是通过鉴定与特定染色体区域相关的脂质相关位点，提高我们对与2型糖尿病相关的脂质异常的理解。确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，为患心脏病风险最高的个体提供标记，并可能导致改善血脂异常的治疗策略。

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.