Cardiac Amyloidosis in Aging African American

描述（由申请人提供）：如果不考虑与获得护理相关的因素，相对于其他群体，非裔美国人心血管疾病死亡率的增加是由于某些疾病的频率增加，对影响所有种族的疾病的质量不同的心脏反应，以及对充血性心力衰竭治疗的相对较差的反应。未确诊、共存、相对普遍、治疗难治性心肌病可能是部分原因。在过去的四年中，我们已经表明，由于血清转甲状腺素蛋白（TTR）中122位的VAL被ILE取代，一种由遗传决定的迟发性淀粉样变性导致了这种种族差异。我们已经证明，这种等位基因在没有非洲血统的个体中极为罕见。在美国东北部、东南部、中西部和西南部（以及非洲的许多地区），非洲裔美国人的患病率（3-4%）是独立确定的。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。在纽约心脏协会III级和IV级充血性心力衰竭的65岁以上非裔美国人中，有10%存在这种等位基因，即使是熟练的心脏病专家也常常无法识别。在目前的病例对照研究中，基因携带者显示出许多心脏淀粉样变性的特征性临床特征，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，并定义等位基因携带者队列中从疾病出现之前的年龄到临床危险时的疾病临床特征出现率。我们与化学领域的同事一起开发了一种小分子，可以在试管和组织培养中抑制转甲状腺素淀粉样蛋白的形成。目前提出的研究将描述该疾病的自然历史和临床外显率，并将为临床试验奠定基础，这些化合物在临床前研究中被发现对这种遗传疾病的治疗和预防有效，这种遗传疾病由100万至150万非洲裔美国人携带的基因编码。非裔美国人比白人美国人患心血管疾病的风险更高。我们已经在3-4%的非裔美国人身上发现了一种基因，这种基因与60岁以后出现的心脏淀粉样变性有关。我们已经证明，所有的基因携带者在心脏上都有与疾病相关的生理变化，但我们还没有确定这些变化是否总是与功能异常有关。目前的建议将确定基因携带者是否有心功能受损的证据，以及哪些异常标记可用于测量进展或对旨在预防或逆转这一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.