前驱流感样疾病与特发性扩张型心肌病的发病：DCM精准医学研究
Antecedent Flu-Like Illness and Onset of Idiopathic Dilated Cardiomyopathy: The DCM Precision Medicine Study.
作者信息
Ni Hanyu, Cao Jinwen, Kinnamon Daniel D, Jordan Elizabeth, Haas Garrie J, Hofmeyer Mark, Kransdorf Evan P, Diamond Jamie, Owens Anjali, Lowes Brian, Stoller Douglas, Tang W H Wilson, Drazner Mark H, Shah Palak, Wilcox Jane E, Katz Stuart D, Jimenez Javier, Shore Supriya, Judge Daniel P, Mead Jonathan O, Cowan Jason, Parker Patricia K, Huggins Gordon S, Hershberger Ray E
机构信息
Division of Human Genetics, Department of Internal Medicine (H.N., J. Cao, D.D.K., E.J., J.O.M., J. Cowan, P.K.P., R.E.H.), The Ohio State University, Columbus.
Davis Heart and Lung Research Institute (H.N., J. Cao, D.D.K., E.J., G.J.H., J.M., J. Cowan, P.P., R.E.H.), The Ohio State University, Columbus.
出版信息
Circ Heart Fail. 2025 May;18(5):e012602. doi: 10.1161/CIRCHEARTFAILURE.124.012602. Epub 2025 Apr 14.
BACKGROUND
Previous studies have speculated that a viral infection may act as a trigger in the development of idiopathic dilated cardiomyopathy (DCM) among individuals genetically at risk. This study aims to describe the frequency of patients with DCM who reported experiencing symptoms of flu-like illness before their DCM diagnosis and to examine if this experience modified the association between genetics and DCM.
METHODS
We analyzed data from the family-based cross-sectional DCM Study conducted between 2016 and 2021. Self-reported symptoms of flu-like illness proximal to DCM diagnosis were obtained from patient interviews. Exome sequencing identified rare variants (pathogenic, likely pathogenic, or variant of uncertain significance) in DCM genes. In a case-only design, logistic mixed models were used to examine if flu-like illness modified the effect of these rare variants on DCM risk. Firth logistic regression was used to examine if flu-like illness modified the effect of each of 13 400 141 common autosomal variants (minor allele frequency ≥1%) on DCM risk.
RESULTS
Of 1164 patients with DCM, 30.2% reported symptoms of flu-like illness proximal to DCM diagnosis. The percentage of patients with antecedent flu-like illness by variant classification was 30.0% for pathogenic/likely pathogenic, 29.6% for variant of uncertain significance only, and 30.0% for no pathogenic/likely pathogenic/variant of uncertain significance. Antecedent flu-like illness was not found to modify the effect of carrying any pathogenic, likely pathogenic, or variant of uncertain significance variants on DCM risk (interaction relative risk, 0.9 [95% CI, 0.7-1.3]). However, significant modification of the effect of rs2102158 (3q24) by antecedent flu-like illness (=2.74×10) was identified by case-only genome-wide association study.
CONCLUSIONS
Approximately one-third of patients with DCM experienced flu-like illness symptoms before DCM diagnosis. We did not find evidence that a flu-like illness modified the effect of rare variants on DCM risk; however, our genome-wide association study analysis suggested that flu-like illness may modify the effect of a common variant on DCM risk.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.
背景
既往研究推测，病毒感染可能是有遗传风险个体发生特发性扩张型心肌病（DCM）的触发因素。本研究旨在描述在DCM诊断前报告有流感样疾病症状的DCM患者的比例，并检验这种经历是否改变了遗传因素与DCM之间的关联。
方法
我们分析了2016年至2021年期间进行的基于家庭的横断面DCM研究的数据。通过患者访谈获取DCM诊断前近期自我报告的流感样疾病症状。外显子组测序确定DCM基因中的罕见变异（致病性、可能致病性或意义未明变异）。在仅病例设计中，使用逻辑混合模型检验流感样疾病是否改变这些罕见变异对DCM风险的影响。使用Firth逻辑回归检验流感样疾病是否改变13400141个常见常染色体变异（次要等位基因频率≥1%）中每一个对DCM风险的影响。
结果
在1164例DCM患者中，30.2%报告在DCM诊断前有流感样疾病症状。按变异分类，有既往流感样疾病的患者比例在致病性/可能致病性变异组为30.0%，仅意义未明变异组为29.6%，无致病性/可能致病性/意义未明变异组为30.0%。未发现既往流感样疾病改变携带任何致病性、可能致病性或意义未明变异对DCM风险的影响（交互相对风险，0.9[95%CI，0.7 - 1.3]）。然而，仅病例全基因组关联研究发现，既往流感样疾病对rs2102158（3q24）的影响有显著改变（=2.74×10）。
结论
约三分之一的DCM患者在DCM诊断前有流感样疾病症状。我们未发现证据表明流感样疾病改变罕见变异对DCM风险的影响；然而，我们的全基因组关联研究分析提示，流感样疾病可能改变常见变异对DCM风险的影响。
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