Heart, Lung and Vascular Institute, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio.
Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, Illinois.
JAMA Cardiol. 2018 Jun 1;3(6):481-488. doi: 10.1001/jamacardio.2018.0618.
The genetic variant MYBPC3Δ25bp occurs in 4% of South Asian descendants, with an estimated 100 million carriers worldwide. MYBPC3 Δ25bp has been linked to cardiomyopathy and heart failure. However, the high prevalence of MYBPC3Δ25bp suggests that other stressors act in concert with MYBPC3Δ25bp.
To determine whether there are additional genetic factors that contribute to the cardiomyopathic expression of MYBPC3Δ25bp.
DESIGN, SETTING, ANDPARTICIPANTS: South Asian individuals living in the United States were screened for MYBPC3Δ25bp, and a subgroup was clinically evaluated using electrocardiograms and echocardiograms at Loyola University, Chicago, Illinois, between January 2015 and July 2016.
Next-generation sequencing of 174 cardiovascular disease genes was applied to identify additional modifying gene mutations and correlate genotype-phenotype parameters. Cardiomyocytes derived from human-induced pluripotent stem cells were established and examined to assess the role of MYBPC3Δ25bp.
In this genotype-phenotype study, individuals of South Asian descent living in the United States from both sexes (36.23% female) with a mean population age of 48.92 years (range, 18-84 years) were recruited. Genetic screening of 2401 US South Asian individuals found an MYBPC3Δ25bpcarrier frequency of 6%. A higher frequency of missense TTN variation was found in MYBPC3Δ25bp carriers compared with noncarriers, identifying distinct genetic backgrounds within the MYBPC3Δ25bp carrier group. Strikingly, 9.6% of MYBPC3Δ25bp carriers also had a novel MYBPC3 variant, D389V. Family studies documented D389V was in tandem on the same allele as MYBPC3Δ25bp, and D389V was only seen in the presence of MYBPC3Δ25bp. In contrast to MYBPC3Δ25bp, MYBPC3Δ25bp/D389V was associated with hyperdynamic left ventricular performance (mean [SEM] left ventricular ejection fraction, 66.7 [0.7%]; left ventricular fractional shortening, 36.6 [0.6%]; P < .03) and stem cell-derived cardiomyocytes exhibited cellular hypertrophy with abnormal Ca2+ transients.
MYBPC3Δ25bp/D389V is associated with hyperdynamic features, which are an early finding in hypertrophic cardiomyopathy and thought to reflect an unfavorable energetic state. These findings support that a subset of MYBPC3Δ25bp carriers, those with D389V, account for the increased risk attributed to MYBPC3Δ25bp.
在南亚裔后裔中，MYBPC3Δ25bp 基因变异的发生率为 4%，全球估计有 1 亿名携带者。MYBPC3Δ25bp 与心肌病和心力衰竭有关。然而，MYBPC3Δ25bp 的高流行率表明，其他应激因素与 MYBPC3Δ25bp 协同作用。
确定是否存在其他遗传因素导致 MYBPC3Δ25bp 的心肌病表现。
设计、地点和参与者：在美国生活的南亚裔个体接受了 MYBPC3Δ25bp 的筛查，并于 2015 年 1 月至 2016 年 7 月在伊利诺伊州芝加哥市的洛约拉大学，对亚组个体进行了心电图和超声心动图的临床评估。
对 174 种心血管疾病基因进行了下一代测序，以确定其他修饰基因的突变，并将基因型-表型参数相关联。建立了源自人诱导多能干细胞的心肌细胞，并进行了检查，以评估 MYBPC3Δ25bp 的作用。
在这项基因型-表型研究中，我们招募了来自美国的南亚裔个体，男女比例为 36.23%（女性），平均人口年龄为 48.92 岁（范围为 18-84 岁）。对 2401 名美国南亚裔个体进行了遗传筛查，发现 MYBPC3Δ25bp 携带者的频率为 6%。与非携带者相比，MYBPC3Δ25bp 携带者中 TTN 错义变异的频率更高，确定了 MYBPC3Δ25bp 携带者群体内的不同遗传背景。引人注目的是，9.6%的 MYBPC3Δ25bp 携带者还存在一种新的 MYBPC3 变异，即 D389V。家系研究记录到 D389V 与 MYBPC3Δ25bp 位于同一等位基因上，并且仅在存在 MYBPC3Δ25bp 时才可见到 D389V。与 MYBPC3Δ25bp 不同，MYBPC3Δ25bp/D389V 与左心室高动力性能相关（平均[SEM]左心室射血分数，66.7[0.7%]；左心室缩短分数，36.6[0.6%]；P<.03），并导致源自干细胞的心肌细胞出现异常的 Ca2+瞬变。
MYBPC3Δ25bp/D389V 与高动力特征相关，这是肥厚型心肌病的早期发现，被认为反映了不利的能量状态。这些发现支持了一小部分携带 MYBPC3Δ25bp 的个体，即携带 D389V 的个体，解释了归因于 MYBPC3Δ25bp 的更高风险。
