MITOCHONDRIA AND METABOLIC SYNDROME IN A SOUTHERN CALIFORNIA CHINESE COHORT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 自从13年前我们的实验室首次将2型糖尿病与一个三代母系的线粒体DNA重排联系起来以来，越来越多的人支持我们的假设，即线粒体功能障碍在2型糖尿病(DM)和重叠代谢综合征(MS)的病因中起着重要作用。通过这项研究，我们计划通过对线粒体DNA(MtDNA)中有害序列变异可能导致的线粒体氧化磷酸化(OXPHOS)缺陷的广泛调查，大大扩展该领域的现有知识。这些导致糖尿病的mtDNA变异被认为范围从最近的相对严重的突变导致家族性DM&MS的大量OXPHOS缺陷到古老的相对轻微的多态导致部分OXPHOS缺陷并增加患DM&MS的风险。 为了验证这一假设，我们建议分析现有的台湾中国家庭样本的mtDNA，这些样本显示DM和MS的母系传播，以及大约500名台湾中国人非家族性DM/MS病例和对照的mtDNA突变，以确定致病原因。这项研究旨在寻找共同的亚洲线粒体DNA谱系(单倍群)与多发性硬化症和糖尿病易感性之间的联系。台湾样本队列将不包括在此IRB申请中，但将属于已提交给调查审查委员会的另一份豁免地位申请。(已递交申请11/01/05)。 一旦在台湾人群中发现与糖尿病相关的mtDNA突变和多态，就需要确认亚洲mtDNA变异与DM和MS之间的相关性的稳健性。为此，也为了控制环境影响，我们将从南加州华裔人群中招募总共500名DM&MS患者和未受影响的对照组，并对他们进行家族性mtDNA突变筛查，以及亚洲特有单倍组与DM&MS之间的关联。这组患者将在当前的应用程序下获得同意。所有登记的DM/MS患者将由UCI医学中心的王平博士确定。正常对照人员将使用名单服务器、UCI网站以及其他招聘材料(即传单)进行招聘。所有研究参与者都需要根据性别、年龄、体重、身高、体重/身高比、体重指数(BMI)、出现症状的年龄(患者)和高血压来确定特征。需要提交空腹血糖(AC)、负荷后血糖(PC)、血甘油三酯(TG)、总胆固醇(TCHO)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、血肌酐(Cre)、血红蛋白A1C(HbA1C，糖化血红蛋白)的血样。此外，还需要用于产生DNA的血液样本，并将用于所有线粒体DNA分析。这项提案不包括除抽血以外的其他侵入性程序。 南加州DM和MS患者中最多15名患者的子集，被发现具有促成线粒体DNA变异，然后将被提供参与更广泛的生理调查。如果有兴趣，这些患者将被纳入我们的主方案：线粒体代谢先天错误和线粒体疾病中的ANT缺陷；主方案(IRB#2002-2608)。随后对这组患者进行广泛的临床、生理和生化特征鉴定，以查明与DM&MS相关的线粒体缺陷(S)的性质。一旦确定这些患者的线粒体缺陷(S)，这些数据将被用于开发两种无创性筛选工具来检测DM&MS患者的线粒体缺陷：微量有机呼气试验(MOBT)用于评估患者的代谢状态；经皮近红外光谱分析(TDNIRS)用于评估肌肉线粒体的OXPHOS功能。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Since our laboratory's initial linkage of Type 2 diabetes to a mtDNA rearrangement in a three generation maternal pedigree 13 years ago, there has been increasing support for our hypothesis that mitochondrial dysfunction plays an important role in the etiology of Type 2 Diabetes Mellitus (DM) and the overlapping Metabolic Syndrome (MS). With this study we are planning to substantially expand upon the existing knowledge in the field by an extensive investigation of defects in mitochondrial oxidative phosphorylation (OXPHOS) caused potentially by deleterious sequence variants in the mitochondrial DNA (mtDNA). These diabetogenic mtDNA variants are proposed to range from recent, relatively severe, mutations resulting in substantial OXPHOS defects with familial DM & MS to ancient, relatively mild, polymorphisms that result in partial OXPHOS defects and an increase in the risk to develop DM & MS. To test this hypothesis, we propose to analyze the mtDNAs of an existing collection of samples from Taiwan Chinese families, which exhibit maternal transmission of DM & MS as well as approximately 500 Taiwan Chinese DM/MS non familial cases and controls to identify causal pathogenic mtDNA mutations. The study is designed to look for associations between the common Asian mtDNA lineages (haplogroups) and predisposition to MS and DM. The Taiwanese cohort of samples will not be included under this IRB application but will fall under a separate, exempt status application which has been submitted to the Investigational Review Board. (application submitted 11/01/05). Once diabetes associated mtDNA mutations and polymorphisms have been identified in the Taiwanese cohort, the robustness of the association between the Asian mtDNA variants and DM & MS needs to be confirmed. For this and also to control for environmental effects, we will then recruit a total of 500 DM & MS patients and unaffected controls from the Southern California Chinese population and screen them for the familial mtDNA mutations and for associations between Asian-specific haplogroups and DM & MS. This cohort of patients will be consented under the current application. All of the enrolled DM/ MS patients will be ascertained by Dr Ping Wang of the UCI Medical Center . Normal controls will be recruited using listservs, the uci website as well as other recruitment materials (i.e. flyers). All study participants will need to be characterized by sex, age, weight, height, weight/height ratio, body mass index (BMI), age of onset of symptoms (in patients) and hypertension. A blood samples for fasting blood glucose (AC), post-loading blood glucose (PC), blood triglyceride levels (TG), total blood cholesterol (TCHO), low density lipoprotein (LDL), high density lipoprotein (HDL), blood creatinine (Cre), hemoglobin A1C (HbA1C, glycated hemoglobin) needs to be submitted. In addition a blood sample for generation of DNA is required and will be used for all mtDNA analyses. No invasive procedures other than blood draw are included in this proposal. A subset of up to 15 patients of the Southern California DM & MS patients, found to have contributory mtDNA variants, will then be offered to participate in more extensive physiological investigations. If interested these patients will be enrolled into our Master Protocol : Mitochondrial Inborn Errors of Metabolism and ANT Defects in Mitochondrial Diseases; A Master Protocol (IRB # 2002-2608). This group of patients is then extensively characterized clinically, physiologically, and biochemically to clarify the nature of the mitochondrial defect(s) associated with DM & MS. Once the mitochondrial defect(s) of these patients has been defined, the data will be used to develop two non-invasive screening tools to detect mitochondrial defects in DM & MS patients: Micro-Organic Breath Test (MOBT) to evaluate the patient's metabolic status and Trans-Dermal Near Infrared Spectroscopy (TDNIRS) to assess muscle mitochondrial OXPHOS function.