Antecedent flu-like illness and onset of idiopathic dilated cardiomyopathy: The DCM Precision Medicine Study

ABSTRACT 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 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 interview. 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 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 1,164 DCM patients, 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 P/LP, 29.6% for VUS only, and 30.0% for no P/LP/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 =0.9, 95% CI: 0.7-1.3). However, significant modification of the effect of rs2102158 (3q24) by antecedent flu-like illness (p=2.74×10 −8 ) was identified by case-only genome-wide association study (GWAS). Conclusions Approximately one-third of DCM patients experienced flu-like illness symptoms prior to DCM diagnosis. We did not find evidence that a flu-like illness modified the effect of rare variants 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 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. 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. A clinical presentation of DCM following a flu-like illness does not signal a higher or lower rare variant genetic risk for DCM and thus does not alter the need for recommended genetic testing. 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.