Mitochondrial Variation and risk of T2DM

线粒体变异和 T2DM 风险

• 批准号: 6924607
• 负责人: RICHA SAXENA
• 金额: $ 5.35万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6924607
• 关键词: African American; bioenergetics; caucasian American; clinical research; diabetes mellitus genetics; gene mutation; genetic regulation; genotype; human genetic material tag; human population genetics; human tissue; mass spectrometry; matrix assisted laser desorption ionization; mitochondrial DNA; mitochondrial disease /disorder; noninsulin dependent diabetes mellitus; oxidative phosphorylation; postdoctoral investigator; single nucleotide polymorphism

DESCRIPTION (provided by applicant): Genetic factors strongly influence the risk of type II diabetes, a complex trait affecting 5-10% of the US population. Multiple lines of evidence point to a role of mitochondrial variation in risk of type II diabetes. Mitochondria are essential components of insulin secretion pathways in pancreatic beta cells and of insulin sensitivity in muscle and liver cells. A rare, maternally inherited form of type II diabetes is caused by a mitochondrial gene mutation, and differential expression studies indicate lower levels of oxidative 3hosphorylation pathway genes in diabetic muscle. The broad goal of this research is to characterize the causal role, if any of inherited variations in the OXPHOS pathway in common T2DM. The objective of this research proposal is to comprehensively examine common variation in key mitochondrial and nuclear-encoded OXPHOS genes, and identify the role of OXPHOS variation on susceptibility to RMR, a quantitative trait reflecting cell energetics, and to type II diabetes. Common variation in mitochondrial lineages and OXPHOS pathway genes will be catalogued, and tested, both singly and in combination, for genetic association to RMR and to T2DM in well powered studies.

描述（由申请人提供）：遗传因素强烈影响II型糖尿病的风险，这是一种影响美国人口5-10％的复杂特征。多行证据表明线粒体变异在II型糖尿病风险中的作用。线粒体是胰岛β细胞中胰岛素分泌途径的必不可少的成分，以及肌肉和肝细胞中胰岛素敏感性的基本成分。 II型糖尿病的一种罕见的，母体遗传的形式是由线粒体基因突变引起的，差异表达研究表明糖尿病肌肉中氧化3磷酸化途径的水平较低。这项研究的广泛目的是表征因果关系，如果遗传性的遗传变化中的oxphos途径中的任何遗传变化。这项研究建议的目的是全面检查关键线粒体和核编码的Oxphos基因的共同变化，并确定Oxphos变异对RMR易感性的作用，RMR的易感性，反映细胞能量的定量性状以及II型糖尿病的作用。线粒体谱系和OXPHOS途径基因的常见变异将被分类，并在良好的研究中进行遗传关联和与T2DM进行分类和测试。