ACQUIRED & GENETIC DETERMINANTS OF MULTIPLE SCLEROSIS

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年至1992年，收集了1294对受多发性硬化症影响的北美双胞胎，从受影响和未受影响的个体中独立收集了详细的医疗记录，暴露和残疾信息，并随后进行了新诊断和新记录的随访。 另外一组195对受影响的加州本地居民双胞胎已被确定在一个队列中的41,000双胞胎参加了基于人口的登记。 所有病例的最新情况都将完成，诊断将使用额外的记录进行系统验证，并将收集特定年龄的残疾信息。 将采集每对成员和特定家族成员（作为对照）的血液标本。 将受影响的双胞胎与其未受影响的同卵双胞胎在感染和其他暴露的历史证据和特征（如内源性雌激素产生的生殖证据）方面进行比较。 将病例与同卵双胞胎和家庭成员对照进行比较，以获得过去感染肺炎衣原体和疱疹病毒家族成员的血清学证据。 我们将比较病例与亲属在HLA（DR）基因座以及其他各种候选基因座等位基因的患病率，这些等位基因是通过全基因组筛选发现的，或者影响免疫能力、髓鞘碱性蛋白和其他相关功能。 仅在病例集中，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。 如果确定了与获得性暴露和基因组的联系，在有足够把握度的情况下，将评估特定的基因-环境相互作用。 病因和进展的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。

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.