New study finds that rare genetic variants significantly increase the risk of atrial fibrillation

In a recent study published in the journal JAMA Cardiology, a group of researchers identified rare predicted loss-of-function variants associated with atrial fibrillation (AF) and elucidated their role in the risk of AF, cardiomyopathy, and heart failure (HF) in combination with a polygenic risk score (PRS).

Study: Rare and common genetic variation underlying atrial fibrillation risk. Image credit: hywards / Shutterstock

Background

AF is the most common cardiac arrhythmia associated with increased risk of stroke, HF, and premature death. While genome-wide association studies (GWAS) have identified common genetic variants associated with AF, pinpointing specific causative genes remains a significant challenge. Rare coding variants, however, often have large effects on disease risk and prognosis, which may be clinically relevant. Recent studies suggest genetic testing for certain subpopulations of AF. Further research is needed to better understand the genetic underpinnings of AF, especially the impact of rare variants, to increase risk stratification and to develop targeted therapies.

About the study

The current study was conducted at the United Kingdom (UK) Biobank and followed the Strengthening Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Participants gave informed consent and ethical approval was obtained. The UK Biobank includes genetic and clinical data on around 500,000 individuals. Rare coding variants were analyzed using gene-based burden tests, focusing on predicted rare loss-of-function (pLOF) variants in 17,979 genes. Secondary tests for rare missense variants were also performed.

Variants with minor allele frequencies below 1% were included, excluding gene masks with cumulative allele counts below 10. Associations were tested using genome-wide regression, adjusting for age, sex and principal components, with significance of set at P < 2.77 × 10^-6. Sensitivity analyzes and replication in external datasets ensured robustness. Protein and Ribonucleic Acid Expression (RNA) was assessed for genes with significant pLOF variants.

PRS was calculated for the influence of common genetic variation, normalized to a mean of 0 with a standard deviation (SD) of 1. Odds ratios (OR) for AF were derived from logistic regression models. Risks of incident AF, cardiomyopathy, and HF were estimated using Cox regression models, adjusted for clinical risk factors, with follow-up until AF diagnosis, death, or study termination.

Results of the study

The study performed gene-based association tests on the exome of 403,990 individuals. Baseline characteristics showed a mean age of 58 years, with 54.1% female participants. A total of 31,124 people with AF were defined as cases, while 372,871 served as controls. Significant associations between AF and pLOF variants were found in Plakophilin 2 (PKP2), Catenin Alpha 3 (CTNNA3), Chromosome 10 Open Reading Frame 71 (C10orf71), Lysine Demethylase 5B

(KDM5B), Titin (TTN) and Ribosomal Protein L3 (RPL3L) genes. Associations for TTN and RPL3L have been reported previously. These findings were replicated in an external cohort of 17,910 individuals with AF and 149,348 controls. Protein and RNA expression analyzes showed that most of the associated genes were predominantly expressed in cardiomyocytes.

Secondary analyzes focused on pLOF variants in cardiac TTN isoforms and constitutively expressed exons, revealing an even greater OR for AF. Additionally, secondary gene-based tests for rare missense variants identified an association with Ubiquitination Factor E4B (UBE4B). Sensitivity analyzes confirmed the robustness of the results, except for RPL3L and UBE4B. PRS analyzes showed a significant OR for AF, with a combined PRS and pLOF variant model showing a significant increase in the OR for AF in high-risk groups. The pooled OR for AF in the high-risk groups was 7.08 (95% CI, 6.03–8.28).

Assessment of AF incidence risk excluded individuals with AF, HF, or dilated cardiomyopathy at baseline. During a median follow-up of 13.3 years, 24,061 individuals were diagnosed with incident AF. Those with a high PRS and a rare pLOF variant had a significantly increased hazard ratio (HR) for incident AF compared with the low-risk groups. Absolute risk analyzes showed a cumulative AF incidence of 28.55% by age 80 years for high-risk individuals, compared with 8.1% for low-risk groups. Sensitivity analyzes in unrelated individuals supported these findings.

Genetic predisposition to AF also affects the risk of HF and cardiomyopathy. Rare pLOF variants in AF-associated genes conferred increased HRs for incident AF, cardiomyopathy, and HF. Exclusion of TTN variants attenuated these effects, particularly for cardiomyopathy and HF. AF PRS was significantly associated with AF but not with cardiomyopathy or HF. In individuals diagnosed with AF after inclusion, rare pLOF variants were associated with an increased HR for cardiomyopathy, but not when excluding TTN variants or considering PRS. In another subgroup with incident cardiomyopathy or HF, no significant associations were found between pLOF or PRS variants and incident AF. Sensitivity analyzes and the application of a 30-day grace period did not significantly change the results.

conclusions

To summarize, in this genetic association study, researchers analyzed whole-exome sequencing data from over 400,000 Biobank participants in the UK, including 31,000 with AF. They identified rare pLOF variants in several genes, significantly increasing the risk of AF. The combination of PRS with these rare variants further increased the risk of incident AF. New associations with CTNNA3 and KDM5B were found, while associations with TTN and PKP2 were confirmed. Findings suggest that inclusion of common and rare genetic variations may enhance AF risk stratification, supporting genetic testing in specific patient groups, particularly those with early-onset AF.