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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Zieman, Susan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Buxbaum, Joel N; Ruberg, Frederick L (2017) Transthyretin V122I (pV142I)* cardiac amyloidosis: an age-dependent autosomal dominant cardiomyopathy too common to be overlooked as a cause of significant heart disease in elderly African Americans. Genet Med 19:733-742
Jacobson, Daniel R; Alexander, Alice A; Tagoe, Clement et al. (2016) The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa. Mol Genet Genomic Med 4:548-56
Kurian, Sunil M; Novais, Marta; Whisenant, Thomas et al. (2016) Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific Signatures. Theranostics 6:1792-809
Quarta, C Cristina; Buxbaum, Joel N; Shah, Amil M et al. (2015) The amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med 372:21-9
Jacobson, Daniel R; Alexander, Alice A; Tagoe, Clement et al. (2015) Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14?333 African-Americans. Amyloid 22:171-4
Buxbaum, Joel N; Linke, Reinhold P (2012) A molecular history of the amyloidoses. J Mol Biol 421:142-59
Bourgault, Steve; Choi, Sungwook; Buxbaum, Joel N et al. (2011) Mechanisms of transthyretin cardiomyocyte toxicity inhibition by resveratrol analogs. Biochem Biophys Res Commun 410:707-13
Jacobson, Daniel; Tagoe, Clement; Schwartzbard, Arthur et al. (2011) Relation of clinical, echocardiographic and electrocardiographic features of cardiac amyloidosis to the presence of the transthyretin V122I allele in older African-American men. Am J Cardiol 108:440-4
Buxbaum, Joel; Alexander, Alice; Koziol, James et al. (2010) Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J 159:864-70
Buxbaum, Joel; Anan, Intissar; Suhr, Ole (2010) Serum transthyretin levels in Swedish TTR V30M carriers. Amyloid 17:83-5

Showing the most recent 10 out of 20 publications