ACQUIRED & GENETIC DETERMINANTS OF MULTIPLE SCLEROSIS

获得

• 批准号: 7072292
• 负责人: THOMAS McCulloch MACK
• 金额: $ 37.67万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7072292
• 关键词: Herpesviridae disease; chlamydial disease; disease /disorder etiology; disease /disorder onset; estrogens; family genetics; gene environment interaction; genetic polymorphism; genetic susceptibility; histocompatibility antigens; human subject; immunogenetics; major histocompatibility complex; medical records; multiple sclerosis; myelin basic proteins; nervous system disorder epidemiology; patient oriented research; remission /regression; twin /multiplet

The long-term goal of this proposal is to identify links between specific environmental exposures and/or specific gene alleles, and multiple sclerosis onset and progression. A cohort of 1294 pairs of North American twins affected by multiple sclerosis was assembled from 1980-92, detailed medical records, exposure and disability information were gathered independently from affected and unaffected individuals, and follow-up for new diagnoses and new records has subsequently proceeded. An additional set of 195 pairs of affected California native resident twins has been identified within a cohort of 41,000 twins participating in a population-based registry. The up-date on all cases will be completed, diagnoses will be systematically validated using the additional records, and age-specific disability information will be gathered. Blood specimens from both members of each pair and from specific family members as controls will be collected. The affected twins will be compared to their unaffected co-twins with respect to historical evidence of infection and other exposures and characteristics such as reproductive evidences of endogenous estrogen production. Cases will be compared to both co-twins and family member controls with respect to serological evidence of past infection with Chlamydia pneumoniae and members of the herpes virus family. We will compare cases to relatives with respect to the prevalence of alleles at the HLA (DR) locus as well as at various other candidate loci, found by genome-wide screening or that affect immune competence, myelin basic protein, and other pertinent functions. Within the set of cases only, both environmental and genetic factors will be assessed as determinants of age at onset and age-specific progression. If links to both acquired exposure and genome are identified, given adequate power, specific gene- environment interactions will be assessed. Analyses for both etiology and progression will consist of logistic regression and sub-analyses stratified on gender, zygosity, and HLA (DR) status. Additional descriptive evidence of environmental etiology will also be sought.

该提案的长期目标是确定特定环境暴露和/或特定基因等位基因与多发性硬化症发病和进展之间的联系。 从 1980-92 年起，我们收集了 1294 对受多发性硬化症影响的北美双胞胎，独立于受影响和未受影响的个体收集了详细的医疗记录、暴露和残疾信息，随后对新诊断和新记录进行了随访。 在参与人口登记的 41,000 名双胞胎中，又发现了另外 195 对受影响的加州本地居民双胞胎。 所有病例的更新都将完成，诊断将使用附加记录进行系统验证，并将收集特定年龄的残疾信息。 将收集每对双方成员以及作为对照的特定家庭成员的血液样本。 受影响的双胞胎将与未受影响的双胞胎进行比较，以了解感染的历史证据以及其他暴露和特征，例如内源性雌激素产生的生殖证据。 将就过去感染肺炎衣原体和疱疹病毒家族成员的血清学证据，将病例与同卵双胞胎和家庭成员对照进行比较。 我们将比较病例与亲属的 HLA (DR) 基因座以及通过全基因组筛选发现的或影响免疫能力、髓磷脂碱性蛋白和其他相关功能的各种其他候选基因座等位基因的流行率。 仅在一组病例中，环境和遗传因素将被评估为发病年龄和年龄特异性进展的决定因素。 如果确定了获得性暴露和基因组的联系，则在足够的功率下，将评估特定的基因-环境相互作用。 病因学和进展分析将包括逻辑回归和按性别、接合性和 HLA (DR) 状态分层的子分析。还将寻求环境病因学的其他描述性证据。