GENETIC EPIDEMIOLOGY ALZHEIMER DISEASE IN TWINS

双胞胎阿尔茨海默病的遗传流行病学

• 批准号: 2050269
• 负责人: John C S Breitner
• 金额: $ 114.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-04 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2050269
• 关键词: aging; disease /disorder proneness /risk; dizygotic twins; family genetics; gene expression; genotype; human ecology; human population genetics; human subject; interview; longitudinal human study; molecular pathology; monozygotic twins; nervous system disorder epidemiology; patient /disease registry; prognosis; twin /multiplet; veterans

Alzheimer disease (AD) appears to result from a combination of genetic and environmental determinants, but the nature of these etiologic factors is obscure. To elucidate the causes of AD and their effects, we propose a longitudinal study of this disease in 10,000 twin pairs of the National Academy of Sciences Registry of aging twin veterans. Some 375 cases in 270 twin pairs will be ascertained over 5 years by initial telephone screening of the Registry, with subsequent formal diagnostic assessment and annual follow-up of screen-positive subjects and their co-twins. We will assess influence of genetic factors in AD by comparing age- specific concordance rates in monozygotic (MZ) and dizygotic (DZ) pairs, as well as pairs of unrelated individuals. We will characterize the distributions of onsets in MZ and DZ co-twins after onset in the first twin. We will estimate the uncensored lifetime risks of AD among MZ or DZ twins of affected individuals; if (as some studies suggest) AD is a Mendelian dominant trait with complete but age-dependent penetrance, these risks should approach 100% and 50% respectively. We will also investigate variability of onset due to heterogeneity of genetic determinants, and variability due to varying environmental influences, by contrasting within-pair and among-pair variation of AD onset times in MZ pairs, and by application of methods relying on age-specific concordance data in both MZ and DZ pairs. We will examine effects of genetic background on timing of onset by contrasting onset variability among concordant DZ vs. MZ pairs. We will investigate possible variations in genetic loading for AD among different ethnic groups by comparing incidence and prevalence among several ethnic groups in the Registry. Even in MZ twin pairs, age at onset of AD can vary substantially. This fact suggests that non-genetic factors may influence onset, and we will therefore examine other host or environmental risk factors for AD by comparing risk factor exposures in discordant MZ pairs whose genotype, an otherwise strong risk factor, is identical. We will further examine the relationship of such risk factors to onset differences in MZ pairs, and test whether risk factors operate by accelerating onset of disease in susceptible individuals. Finally, we will examine whether the above genetic and/or environmental factors may influence variations in course and progression of disease, as they may act on onset. This study will complement the current molecular search for genes that predispose to AD by examining evidence to support or refute such genetic influences, by investigating the age-dependent expression of AD (and hence its predisposing genes, if such exist), and by studying the possible influence of non-genetic host or environmental factors on disease expression. Even if susceptibility to AD proves ultimately to be genetically determined, this study holds potential for the identification of two important strategies for prevention, delay of disease onset and amelioration of clinical course, which may make possible substantial reduction in attendant morbidity.

阿尔茨海默病 (AD) 似乎是遗传因素综合作用的结果 和环境决定因素，但这些病因的本质 因素不详。 为了阐明 AD 的原因及其影响，我们 提议对 10,000 对双胞胎进行一项针对这种疾病的纵向研究 美国国家科学院老年双胞胎退伍军人登记处。 约 375 270 对双胞胎的病例将在 5 年内通过初步确定 登记处的电话筛查，随后进行正式诊断 对筛查呈阳性的受试者及其情况进行评估和年度随访 同卵双胞胎。 我们将通过比较年龄来评估遗传因素对 AD 的影响 单卵（MZ）和双卵（DZ）对的特定一致性率， 以及成对的不相关的个​​体。 我们将表征 同卵双胞胎和异卵双胞胎中第一对双胞胎发病后的发病分布 双。 我们将估计 MZ 或 MZ 中未经审查的终生 AD 风险 受影响个体的异卵双胞胎；如果（正如一些研究表明的那样）AD 是 孟德尔显性特征具有完全但与年龄相关的外显率， 这些风险应分别接近 100% 和 50%。 我们还将 研究由于遗传异质性而导致的发病变异性 决定因素以及由于不同环境影响而导致的变异性， 通过对比 AD 发作时间的组内和组间变化 MZ 对，并通过应用依赖于特定年龄的方法 MZ 和 DZ 对中的一致性数据。 我们将检查以下效果 通过对比发病变异性来了解发病时间的遗传背景 在一致的 DZ 与 MZ 对之间。 我们将调查可能的情况 不同种族群体中 AD 基因负荷的差异 比较几个民族的发病率和患病率 登记处。 即使在同卵双胞胎中，AD 的发病年龄也可能存在很大差异。 这 事实表明非遗传因素可能影响发病，我们将 因此，通过以下方式检查 AD 的其他宿主或环境风险因素： 比较基因型不一致的 MZ 对的风险因素暴露， 另一个强大的风险因素是相同的。 我们将进一步审查 这些风险因素与 MZ 对中发病差异的关系， 并测试危险因素是否会加速疾病的发作 在易感人群中。 最后我们来检验一下上面的情况是否成立 遗传和/或环境因素可能会影响过程的变化 和疾病的进展，因为它们可能在发病时起作用。 这项研究将补充目前对基因的分子搜索 通过检查支持或反驳此类遗传的证据来诱发AD 通过研究 AD 的年龄依赖性表达（以及 因此它的易感基因，如果存在的话），并通过研究 非遗传宿主或环境因素的可能影响 疾病表达。 即使最终证明对AD的易感性 是由基因决定的，这项研究有潜力 确定两项重要的预防策略、延迟策略 疾病的发作和临床病程的改善，这可能使 可能大幅降低伴随发病率。