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Characterizing the impact of race, ethnicity, and genotype on heart failure outcomes in nonischemic cardiomyopathy

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Health Care Inequities and health disparities
  • Secondary Categories:
    • Health Care Inequities and health disparities
Introduction:
Advancements in next-generation sequencing (NGS) has facilitated the identification of disease-causing genetic variants in nonischemic cardiomyopathy (NiCM). Several studies have found that a causative variant can be identified in 20-50% of idiopathic NiCM cases. Ethnic and racial minorities are underrepresented in human genomic studies and disease course is less well described in these groups. This study aims to characterize differences in NiCM outcomes between groups underrepresented in human genomic reference populations and studies (UR) compared to non-Hispanic whites (NHW), stratifying by genotype. 

 

Methods:
This was a single-center, retrospective study of patients at the University of California, San Diego who had genetic testing completed for presumed NiCM from 2018 – 2022. Demographic information and echocardiogram data was manually extracted from the electronic health record and input into a RedCap dataset. Primary outcome was a composite heart failure (HF) outcome that included cardiac transplantation, Left Ventricle Assist Device Placement (LVAD), or HF death. Analysis was stratified by underrepresented group status and by genotype. Patients with a variant classified as pathogenic or likely pathogenic were considered genotype (+), while those with a Variant of Unknown Significance (VUS), benign or likely benign variant, or no variants detected were classified as genotype (-). Data analysis was performed using STATA.

 

Results:
There were 365 total patients included in the analysis, 225 UR patients and 140 NHW patients. There was no difference in genotype positivity between UR patients and NHW patients (genotype (+): UR = 17.3%, NHW = 17.9%). Genotype (+) UR patients had the youngest mean age at diagnosis (45.2 years), followed by genotype (-) UR patients (48.3 years), then genotype (-) NHW patients (55.3 years), and genotype (+) NHW patients (58.6 years) (p <0.001).  Genotype (+) patients experienced more HF events overall than genotype (-) patients (39.1% vs. 23.3%, p = 0.009). When stratified by underrepresented status, genotype (+) UR patients had the highest rate of HF events (41.0%), followed by genotype (+) NHW patients (36.0%), genotype (-) UR patients (26.3%), and lastly genotype (-) NHW patients (18.3%) (p = 0.024).   

 

Genotype (+) patients had worse outcomes than genotype (-) patients in time-to-event analysis regardless of UR status (median age: 68.9 vs. 74.7, p = 0.029). When patients were stratified by UR status in the absence of genetic data, UR patients had worse HF outcomes in time-to-event analysis (p = <0.001). In time-to-event analysis, genotype (+) UR patients had the worst overall outcomes (median age = 63 years), followed by genotype (-) UR patients (median age = 69 years), and subsequently genotype (+) NHW patients (median age = 72.4) and lastly genotype (-) NHW patients.

 

Conclusion:
In patients with NiCM, underrepresented status and genotype positivity are associated with increased HF outcomes. In both NHW and UR populations, genotype positivity is associated with worse outcomes, consistent with previous literature. Analysis stratifying by underrepresented status and genotype suggests higher severity of disease in UR patients when compared to NHW patients. Genotype (+) UR patients have a higher burden of HF events, and have earlier HF events in time-to-event analysis than any other group, including genotype (+) NHW patients. Further research is needed to understand if this increased risk is due to uncharacterized genetic risk, which includes polygenic and epigenetic risk. 

 

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