ACQUIRED & GENETIC DETERMINANTS OF MULTIPLE SCLEROSIS

这项建议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年间收集了1294对患有多发性硬化症的北美双胞胎的队列，独立于受影响和未受影响的个人收集了详细的医疗记录、接触和残疾信息，随后进行了新诊断和新记录的后续工作。另一组195对受影响的加州土生土长的双胞胎已经在参与基于人口登记的4.1万对双胞胎队列中被确认。将完成所有病例的最新情况，将使用额外的记录系统地验证诊断，并将收集特定年龄的残疾信息。将收集每对成员和作为对照的特定家庭成员的血液样本。在感染的历史证据和其他暴露和特征方面，受影响的双胞胎将与他们未受影响的同卵双胞胎进行比较，例如内源性雌激素产生的生殖证据。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而言，病例将与同卵双胞胎和家庭成员对照进行比较。我们将比较病例和亲属在人类白细胞抗原(DR)基因座以及其他各种候选基因座的等位基因的流行情况，这些基因座是通过全基因组筛查发现的，或者是影响免疫功能、髓鞘碱性蛋白和其他相关功能的。仅在一组病例中，环境和遗传因素都将被评估为发病年龄和特定年龄进展的决定因素。如果确定了与获得性暴露和基因组的联系，并给出了足够的能力，将评估特定的基因-环境相互作用。对病因和进展的分析将包括Logistic回归和按性别、合子和人类白细胞抗原(DR)状态分层的子分析。还将寻找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.