Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Department of Human Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
JAMA Cardiol. 2018 Oct 1;3(10):929-938. doi: 10.1001/jamacardio.2018.2541.
The prevalence of nonischemic dilated cardiomyopathy (DCM) is greater in individuals of African ancestry than in individuals of European ancestry. However, little is known about whether the difference in prevalence or outcomes is associated with functional genetic variants.
We hypothesized that Bcl2-associated anthanogene 3 (BAG3) genetic variants were associated with outcomes in individuals of African ancestry with DCM.
This multicohort study of the BAG3 genotype in patients of African ancestry with dilated cardiomyopathy uses DNA obtained from African American individuals enrolled in 3 clinical studies: the Genetic Risk Assessment of African Americans With Heart Failure (GRAHF) study; the Intervention in Myocarditis and Acute Cardiomyopathy Trial-2 (IMAC-2) study; and the Genetic Risk Assessment of Cardiac Events (GRACE) study. Samples of DNA were also acquired from the left ventricular myocardium of patients of African ancestry who underwent heart transplant at the University of Colorado and University of Pittsburgh.
The primary end points were the prevalence of BAG3 mutations in African American individuals and event-free survival in participants harboring functional BAG3 mutations.
Four BAG3 genetic variants were identified; these were expressed in 42 of 402 African American individuals (10.4%) with nonischemic heart failure and 9 of 107 African American individuals (8.4%) with ischemic heart failure but were not present in a reference population of European ancestry (P < .001). The variants included 2 nonsynonymous single-nucleotide variants; 1 three-nucleotide in-frame insertion; and 2 single-nucleotide variants that were linked in cis. The presence of BAG3 variants was associated with a nearly 2-fold (hazard ratio, 1.97 [95% CI, 1.19-3.24]; P = .01) increase in cardiac events in carriers compared with noncarriers. Transfection of transformed adult human ventricular myocytes with plasmids expressing the 4 variants demonstrated that each variant caused an increase in apoptosis and a decrease in autophagy when samples were subjected to the stress of hypoxia-reoxygenation.
This study demonstrates that genetic variants in BAG3 found almost exclusively in individuals of African ancestry were not causative of disease but were associated with a negative outcome in patients with a dilated cardiomyopathy through modulation of the function of BAG3. The results emphasize the importance of biological differences in causing phenotypic variance across diverse patient populations, the need to include diverse populations in genetic cohorts, and the importance of determining the pathogenicity of genetic variants.
非缺血性扩张型心肌病（DCM）在非洲裔个体中的患病率高于欧洲裔个体。然而，对于这种患病率或结局差异是否与功能遗传变异有关，人们知之甚少。
我们假设 Bcl2 相关的 anthanogene 3（BAG3）遗传变异与 DCM 非洲裔个体的结局有关。
这项针对非洲裔扩张型心肌病患者 BAG3 基因型的多队列研究利用了来自美国黑人个体的 DNA，这些个体参加了 3 项临床研究：心力衰竭的非洲裔美国人遗传风险评估（GRAHF）研究；心肌炎和急性心肌病治疗-2 试验（IMAC-2）研究；以及心脏事件遗传风险评估（GRACE）研究。从科罗拉多大学和匹兹堡大学接受心脏移植的非洲裔个体的左心室心肌中也获得了 DNA 样本。
主要终点是非洲裔美国人中 BAG3 突变的患病率以及携带功能性 BAG3 突变的参与者的无事件生存情况。
确定了 4 种 BAG3 遗传变异，它们在 402 名非缺血性心力衰竭的非洲裔美国人个体（10.4%）和 107 名缺血性心力衰竭的非洲裔美国人个体（8.4%）中表达，但在欧洲裔参考人群中不存在（P <.001）。这些变异包括 2 种非同义单核苷酸变异、1 种三核苷酸框内插入和 2 种单核苷酸变异，它们在顺式中连锁。BAG3 变异的存在与携带者相比，心脏事件增加近 2 倍（风险比，1.97[95%CI，1.19-3.24]；P =.01）。转染表达 4 种变异体的转化成年人心室肌细胞表明，当样本受到缺氧再氧合应激时，每种变异体都会导致细胞凋亡增加和自噬减少。
这项研究表明，几乎只在非洲裔个体中发现的 BAG3 遗传变异不是疾病的病因，但通过调节 BAG3 的功能，与扩张型心肌病患者的不良结局有关。研究结果强调了生物差异在导致不同患者群体表型变异中的重要性，需要在遗传队列中纳入不同人群，并确定遗传变异的致病性。
