Divisions of Cardiovascular Medicine (R.E.H.), The Ohio State University Wexner Medical Center, Columbus.
Human Genetics (R.E.H., J.C., E.J., D.D.K.), The Ohio State University Wexner Medical Center, Columbus.
Circ Res. 2021 May 14;128(10):1514-1532. doi: 10.1161/CIRCRESAHA.121.318157. Epub 2021 May 13.
Our insight into the diverse and complex nature of dilated cardiomyopathy (DCM) genetic architecture continues to evolve rapidly. The foundations of DCM genetics rest on marked locus and allelic heterogeneity. While DCM exhibits a Mendelian, monogenic architecture in some families, preliminary data from our studies and others suggests that at least 20% to 30% of DCM may have an oligogenic basis, meaning that multiple rare variants from different, unlinked loci, determine the DCM phenotype. It is also likely that low-frequency and common genetic variation contribute to DCM complexity, but neither has been examined within a rare variant context. Other types of genetic variation are also likely relevant for DCM, along with gene-by-environment interaction, now established for alcohol- and chemotherapy-related DCM. Collectively, this suggests that the genetic architecture of DCM is broader in scope and more complex than previously understood. All of this elevates the impact of DCM genetics research, as greater insight into the causes of DCM can lead to interventions to mitigate or even prevent it and thus avoid the morbid and mortal scourge of human heart failure.
我们对扩张型心肌病 (DCM) 遗传结构的多样性和复杂性的认识正在迅速发展。DCM 遗传学的基础在于明显的位置和等位基因异质性。虽然 DCM 在一些家族中表现出孟德尔单基因结构，但我们的研究和其他研究的初步数据表明，至少 20% 至 30% 的 DCM 可能具有寡基因基础，这意味着来自不同非连锁位置的多个罕见变异决定了 DCM 表型。低频和常见的遗传变异也可能与 DCM 的复杂性有关，但在罕见变异的背景下都没有进行过研究。其他类型的遗传变异也可能与 DCM 有关，基因-环境相互作用也已被确定与酒精和化疗相关的 DCM 有关。总的来说，这表明 DCM 的遗传结构比以前理解的范围更广，也更复杂。所有这些都提高了 DCM 遗传学研究的重要性，因为对 DCM 病因的更深入了解可以导致干预措施来减轻甚至预防它，从而避免人类心力衰竭的病态和致命的困扰。
