Cardiac Amyloidosis in Aging African American

描述（由申请人提供）：如果不考虑与获得治疗相关的因素，非裔美国人相对于其他群体的心血管疾病死亡率增加是由于某些疾病的频率增加，对影响所有种族群体的疾病的心脏反应存在质的差异，以及对充血性心力衰竭治疗的反应相对较差。一种未诊断的、共存的、相对普遍的、治疗抵抗性心肌病是一种可能的部分解释。在过去的四年中，我们已经表明，遗传决定的迟发性淀粉样变性的形式，由于ILE取代瓦尔在位置122的血清蛋白甲状腺素运载蛋白（TTR）有助于这种种族差异。我们已经证明，该等位基因在没有记录的非洲遗传的个体中是极其罕见的。其在美国东北部、东南部、中西部和西南部（以及非洲许多地区）的非洲裔美国人中的患病率（3-4%）已被独立确定。我们还获得的数据表明，随着年龄的增长，等位基因频率在社区中下降，这表明它对死亡率有独立的影响。该等位基因存在于10%的65岁以上患有纽约心脏协会III级和IV级充血性心力衰竭的非洲裔美国人中，并且即使是熟练的心脏病专家也经常无法识别。在目前的病例对照研究中，基因携带者显示出心脏淀粉样变性的许多特征性临床特征，其频率在统计学上显著高于年龄、性别和种族匹配的对照组。我们目前的建议旨在独立验证这些发现中的一些，以及定义等位基因携带队列中疾病临床特征的出现率，该队列从疾病出现之前的年龄到他们成为临床风险的时间。我们与化学领域的同事合作，开发出了可以在试管和组织培养中抑制甲状腺素运载蛋白淀粉样蛋白生成的小分子。目前提出的研究将描述该疾病的自然史和临床特征，并将为临床试验的化合物奠定基础，这些化合物在临床前研究中被发现在治疗和预防这种遗传性疾病中有效，这种遗传性疾病由1- 150万非洲裔美国人携带的基因编码。我们已经确定了一种基因，该基因存在于3-4%的非洲裔美国人中，与60岁后出现的心脏病（称为心脏淀粉样变性）相关。我们已经证明，所有该基因的携带者都有与疾病相关的心脏物理变化，但我们还没有确定这些变化是否总是与异常功能有关。本提案将确定基因携带者是否有心脏功能受损的证据，以及哪些异常标志物可用于测量进展或对旨在预防或逆转该过程的新疗法的反应性。

DESCRIPTION (provided by applicant): If factors related to access to care are not considered, the increased mortality from cardiovascular disease in African-Americans relative to other groups is due to the increased frequency of some diseases, a qualitatively different cardiac response to disorders affecting all ethnic groups and a relatively poor response to treatment of congestive heart failure. An undiagnosed, coexistent, relatively prevalent, treatment-resistant cardiomyopathy is a possible partial explanation. During the last four years we have shown that a genetically determined form of late-onset amyloidosis due to a substitution of ILE for VAL at position 122 in the serum protein transthyretin (TTR) contributes to this racial disparity. We have shown that the allele is extremely rare in individuals without documented African heritage. Its prevalence among African-Americans (3-4%) has been independently determined in the Northeast, Southeast, Midwest and Southwestern U.S. (as well in many regions of Africa). We have also obtained data indicating the allele frequency decreases in the community with increasing age, suggesting that it has an independent effect on mortality. The allele is present in 10% of African-Americans over 65 with New York Heart Association grade III and IV congestive heart failure, and is frequently unrecognized even by skilled cardiologists. In a current case control study the gene carriers show many of the characteristic clinical features of cardiac amyloidosis with a statistically significant greater frequency than the age, gender and ethnically matched controls. Our current proposal is designed to independently validate some of these findings as well as defining the rate of appearance of clinical features of the disease in an allele bearing cohort followed from an age prior to the appearance of disease to a time when they become clinically at risk. In conjunction with our colleagues in chemistry we have developed small molecules that can inhibit transthyretin amyloidogenesis in the test tube and in tissue culture. The currently proposed studies will characterize the natural history and clinical penetrance of the disease and will set the stage for clinical trials of compounds found to be effective in pre-clinical studies in both therapy and prophylaxis of this hereditary disorder encoded by a gene carried by 1-1.5 million African- Americans.African-Americans are at greater risk for cardiovascular disease than Caucasian- Americans. We have identified a gene that is present in 3-4% of African-Americans that is associated with a heart disease called cardiac amyloidosis appearing after age 60. We have shown that all the carriers of the gene have physical changes in the heart related to the disease but we have not yet determined if the changes are always associated with abnormal function. The present proposal will establish whether gene carriers have evidence for compromised cardiac function and which markers of abnormality can be used to measure progression or responsiveness to new therapeutics designed to prevent or reverse the process.