Antecedent flu-like illness and onset of idiopathic dilated cardiomyopathy: The DCM Precision Medicine Study
Authors: Ni Hanyu , Cao Jinwen , Kinnamon Daniel D. , Jordan Elizabeth , Haas Garrie , Hofmeyer Mark , Kransdorf Evan , Diamond Jamie , Owens Anjali , Lowes Brian , Stoller Douglas , Tang W. H. Wilson , Drazner Mark , Shah Palak , Wilcox Jane E. , Katz Stuart , Jimenez Javier , Shore Supriya , Judge Daniel P. , Mead Jonathan , Cowan Jason , Parker Patricia , Huggins Gordon S. , Hershberger Ray E. 
Published: October 2024

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 DCM patients who reported experiencing symptoms of flu-like illness prior to their DCM diagnosis and to examine if this experience modified the association between genetics and DCM.

Methods

We analyzed data from the US multi-center DCM Precision Medicine Study conducted between 2016 and 2021. Medical history including self-reported symptoms of flu-like illness proximal to DCM diagnosis was obtained from patient interview or medical record review. Exome sequencing identified rare variants [pathogenic (P), likely pathogenic (LP), or uncertain significance (VUS)] in DCM genes. In a case-only design, logistic mixed models were used to examine if flu-like illness modified the effect of harboring these rare variants on DCM risk. After imputation using the TOPMed Imputation Server, Firth logistic regression was used to examine if flu-like illness modified the effect of each of 13,404,093 common autosomal variants (minor allele frequency ≥1%) on DCM risk.

Results

Of 1,164 DCM patients, 351 (30.2%; 95% CI: 26.2% -34.1%) reported episodes of flu-like illness proximal to their DCM diagnosis. The percentage of patients with antecedent flu-like illness at diagnosis was higher among those at younger age groups (P=0.009) and among smokers than non-smokers (32.4% vs. 28.2%, P=0.04). The percentage by variant classification was 30.0% for LP/P, 29.6% for VUS only, and 30.0% for no LP/P/VUS. Antecedent flu-like illness was not found to modify the effect of carrying any P, LP or VUS variants on DCM risk (interaction relative risk =1.0, 95% CI: 0.7-1.3). However, significant modification of the effect of rs2102158 (3q24) by antecedent flu-like illness (p=1.1e-8) was identified by case-only genome-wide association study (GWAS).

Conclusions

Approximately one-third of patients with DCM reported experiencing symptoms of flu-like illness prior to DCM diagnosis. We did not find evidence that a flu-like illness modified the effect of rare variants in DCM genes on DCM risk; however, our GWAS analysis suggested that flu-like illness may modify the effect of a common variant on DCM risk.

Clinical Perspective

1.

What is new?

This study is the first that provides a comprehensive epidemiologic profile of antecedent flu-like illness among DCM patients of diverse ancestry, recruited from geographically diverse heart failure programs across the United States.

Antecedent flu-like illness was not found to modify the effect of harboring P/LP/VUS rare variants on DCM risk, even though approximately one-third of patients with DCM reported episodes of flu-like illness prior to their DCM diagnosis.

GWAS analysis suggested that flu-like illness may modify the effect of a common variant at chromosome 3q24 on DCM risk.

2.

What are the clinical implications?

Results from this study will inform clinicians that no evidence was found to suggest that a flu-like illness modified the effect of harboring rare variants in DCM genes on DCM risk.

These findings do not address the long-held question of whether the clinical presentation of DCM can be caused by a flu-like illness in some patients; further investigation will be needed.