Heart failure & cardiomyopathiesMeta-analysis
Association of Common Ancestry-Enriched Variants With Cardiomyopathy and Arrhythmias
- Genetic association study (biobank meta-analysis)
- fixed-effects meta-analysis
- 2 biobanks
Authors' conclusion
Large-scale biobank analysis identified variants classified as VUS that conferred increased risk of cardiomyopathy and arrhythmia in individuals with African ancestry. The risk associated with these variants was increased in the presence of cardiovascular risk factors and HF.
Study context
- Population
- Individuals of African ancestry; Variants of uncertain significance (VUS) enriched in African ancestry in 18 cardiomyopathy and arrhythmia genes82 enriched VUS
- Participants
- 96,897 individuals
- Comparison
- Carriers of African ancestry-enriched VUS vs non-carriers
- All of Usn = 65,481
- BioVUn = 31,416
- Outcome
- Association of ancestry-enriched VUS with CV phenotypes
Pooled result
As reported in the abstract
Individual CV phenotypes, per variant (pooled meta-analysis)
Adjusted odds ratio (95% CI)P value
PKP2 p.Val558Ileventricular arrhythmias or SCD
4.02(1.85–8.71)
P = 0.004ELAC2 p.Ile396ValHF
1.67(1.17–2.39)
P = 0.02ELAC2 p.Ile396Valatrial arrhythmias
1.88(1.27–2.78)
P = 0.02FLNC p.Gly11SerHF
1.96(1.24–3.10)
P = 0.02PKP2 p.Val842IleHF
1.99(1.16–3.41)
P = 0.039Per variant, as printed
- Ancestry-enriched VUS identified
- 82
- Variants associated with composite CV outcome (exploratory, All of Us)
- 10
Further pooled results
Earlier onset of heart failure (HF) and atrial arrhythmias with CV risk factors, pooled variant carriers
| Comparison | adjusted hazard ratio (95% CI) | P value | |
|---|---|---|---|
| cardiovascular risk factors · HF | 1.71 (1.25–2.33) | P = 0.0006 | |
| cardiovascular risk factors · atrial arrhythmias | 1.17 (1.06–1.29) | P = 0.0019 | |
| 0.512Adjusted hazard ratio (log scale) |
Arrhythmia burden in participants with HF
- PKP2 p.Val558Ile, SCN5A p.Gln1832Glu and FLNC p.Gly11Ser showed increased arrhythmia burden specifically in HF
ACMG classification
- PKP2 p.Val558Ile met likely pathogenic criteria; estimated Black US adults potentially affected
- 24 000
Original publication
Association of Common Ancestry-Enriched Variants With Cardiomyopathy and Arrhythmias. Circulation. Published 27 May 2026. doi:10.1161/circulationaha.126.080245
Summarised from the published abstract; every number is checked against it