Novel Gene Variants in ME/CFS and Fibromyalgia

ME/CFS 和纤维肌痛的新基因变异

• 批准号: 9216394
• 负责人: Kathleen C Light
• 金额: $ 32.91万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9216394
• 关键词: Affect; Antigens; Autoimmune Process; Biological Markers; Blood specimen; CD100 antigen; Cells; Child; Chronic; Chronic Fatigue Syndrome; Comorbidity; Complex; Cytochrome c Reductase; Cytochromes b; DNA; DNA Sequence Alteration; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Energy-Generating Resources; Fatigue; Fibromyalgia; Fogs; Frequencies; Functional disorder; Gene Expression; Genes; Glucose; Goals; Human; Immune; Individual; Inherited; Insulin; Investigation; Lactic Acidosis; Leukocytes; Link; MELAS Syndrome; Major Depressive Disorder; Mental Depression; Messenger RNA; Methods; Migraine; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Mothers; Muscle Weakness; Mutate; Mutation; Myopathy; NADH; Neuropathy; Oxidative Stress Pathway; Pain; Patients; Positioning Attribute; Predisposition; Production; Proteins; Psyche structure; Research; Research Priority; Respiratory Chain; Risk; Role; Sampling; Severities; Single Nucleotide Polymorphism; Somatic Mutation; Symptoms; Technology; Time; Variant; alpha 1-Antitrypsin; base; exercise intolerance; genetic variant; mitochondrial dysfunction; novel; specific biomarkers; trait; transcriptome; transcriptome sequencing; web site

Myalgic encephalomyelitis/Chronic fatigue syndrome (ME/CFS) and Fibromyalgia syndrome (FM) are chronic multi-symptom disorders, which are frequently comorbid. The primary goal of this study is to identify unique genetic mutations seen in ME/CFS and/or FM but not in depression or other functional disorders like migraine. Identifying such variants would provide specific biomarkers for diagnosis of ME/CFS and FM and for identifying causes and targets for treatment. Both ME/CFS and FM have been proposed to involve mitochondrial dysfunction. Recently, we employed RNA-Seq and VarScan2 to examine mutations in leukocytes (not whole blood) for the full human transcriptome. In a pilot sample, 94% of the 17 ME/CFS patients had High or Moderate Impact variants in mitochondrial genes affecting NADH dehdrogenase 4, and the 17th had mitochondrial variants affecting cytochrome B. Both are proteins in the respiratory chain complexes that have critical roles in production of ATP, the cell's major energy source. Known mitochondrial disorders are associated with other mutations affecting these same complexes. Like ME/CFS, these mitochondrial disorders involve symptoms of muscle weakness, fatigue, neuropathies and exercise intolerance. Most of our 17 patients also had a second mitochondrial variant affecting ATP production and also a chromosomal DNA variant affecting either mitochondrial replication or autoimmune function. Thus, we hypothesize that mutations in mitochondrial genes (especially in combination with other mutations) increase risk or contribute causally to the development of ME/CFS and/or FM, and may be specific biomarkers of these disorders. Specific aims of the study are: First, to use RNA-Seq and VarScan2 to compare the frequency of leukocyte mitochondrial mutations of 150 patients with ME/CFS and/or FM versus 150 healthy controls, patients with migraines or depression (total sample= 300). Second, to examine the relationship between greater heteroplasmy of these mutations and severity of physical fatigue, mental fog and widespread pain in all 150 CFS/ME and FM patients. Third, in mothers of 40 ME/CFS or FM patients with mitochondrial mutations, to assess whether they share their child's mutation, indicating what proportion of patients have maternally inherited vs. acquired somatic mutations.

肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）和纤维肌痛综合征（FM）是 慢性多症状性疾病，通常是共病。本研究的主要目的是 确定在ME/CFS和/或FM中观察到的独特基因突变，但在抑郁症或其他功能性疾病中未观察到 像偏头痛这样的疾病鉴定这些变体将为诊断癌症提供特异性生物标志物。 ME/CFS和FM，并确定治疗的原因和目标。ME/CFS和FM均已 可能与线粒体功能障碍有关最近，我们使用RNA-Seq和VarScan 2来 检查白细胞（不是全血）中的突变，以获得完整的人类转录组。在试点样本中， 17例ME/CFS患者中有94%的患者在线粒体基因中存在高或中度影响变异， NADH脱氢酶4，第17个具有影响细胞色素B的线粒体变体。两者都是 呼吸链复合物中的蛋白质，在细胞主要的ATP生成中起关键作用。 能源。已知的线粒体疾病与其他影响这些相同的突变有关。 配合物像ME/CFS一样，这些线粒体疾病涉及肌肉无力、疲劳、 神经病和运动不耐受。我们的17名患者中的大多数也有第二种线粒体变异 影响ATP的产生，也影响线粒体复制的染色体DNA变体 或自身免疫功能。因此，我们假设线粒体基因突变（特别是在 与其他突变组合）增加风险或导致ME/CFS的发生 和/或FM，并且可以是这些疾病的特异性生物标志物。研究的具体目标是：第一， 使用RNA-Seq和VarScan 2比较150例白细胞线粒体突变的频率 患有ME/CFS和/或FM的患者与150名健康对照者，患有偏头痛或抑郁症的患者（总 样本= 300）。第二，研究这些突变之间的关系， 150例CFS/ME和FM患者的躯体疲劳、精神模糊和广泛疼痛的严重程度。 第三，在40名患有线粒体突变的ME/CFS或FM患者的母亲中， 分享他们孩子的突变，表明有多少比例的患者是母系遗传的， 体细胞突变。