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LMNA Variants and Risk of Adult-Onset Cardiac Disease
Quick Takes
- Rare coding variants in LMNA were significantly associated with atrial fibrillation, bradyarrhythmias, ventricular arrhythmias, dilated cardiomyopathy, and heart failure in middle-aged adults.
- The absolute risk of arrhythmia or cardiomyopathy was substantially higher when rare missense variants occur upstream of the nuclear localization signal in LMNA.
- Additional studies are indicated to understand the susceptibility properties of the rod domain upstream of the nuclear localization signal in LMNA and could be a possible therapeutic target in the future.
Study Questions:
What is the frequency and contribution of rare LMNA variants to cardiomyopathy and arrhythmia risk among ambulatory adults?
Methods:
The investigators included 185,990 UK Biobank participants with whole-exome sequencing for this analysis. They annotated rare loss-of-function and missense LMNA variants for functional effect using 30 in silico prediction tools and assigned a predicted functional effect weight to each variant and calculated a score for each carrier. The authors tested associations between the LMNA score and arrhythmia (atrial fibrillation, bradyarrhythmia, ventricular arrhythmia) or cardiomyopathy outcomes (dilated cardiomyopathy and heart failure). They also examined associations for variants located upstream versus downstream of the nuclear localization signal. Associations between LMNA score and the composite arrhythmia or cardiomyopathy outcome, as well as each component individually (atrial fibrillation, bradyarrhythmia, ventricular arrhythmia, dilated cardiomyopathy, and heart failure) were assessed using multivariable logistic regression with Firth’s penalized likelihood approach.
Results:
Overall, 1,167 (0.63%) participants carried an LMNA variant and 15,079 (8.11%) had an arrhythmia or cardiomyopathy event during a median follow-up of 10.9 years. The LMNA score was associated with arrhythmia or cardiomyopathy (odds ratio [OR], 2.21; p < 0.001) and the association was more significant when restricted to variants upstream of the nuclear localization signal (OR, 5.05; p < 0.001). The incidence rate of arrhythmia or cardiomyopathy was 8.43 per 1,000 person-years (95% CI, 6.73-10.12 per 1,000 person-years) among LMNA variant carriers and 6.38 per 1,000 person-years (95% CI, 6.27-6.50 per 1,000 person-years) among noncarriers. Only three (1.2%) of the variants were reported as pathogenic in ClinVar.
Conclusions:
The authors reported that middle-aged adult carriers of rare missense or loss-of-function LMNA variants are at increased risk for arrhythmia and cardiomyopathy.
Perspective:
This prospective cohort study of middle-aged adults reports that rare coding variants in LMNA were significantly associated with atrial fibrillation, bradyarrhythmias, ventricular arrhythmias, dilated cardiomyopathy, and heart failure. Furthermore, the absolute risk of arrhythmia or cardiomyopathy was substantially higher when rare missense variants occur upstream of the nuclear localization signal in LMNA. Additional studies are indicated to understand the susceptibility properties of the rod domain upstream of the nuclear localization signal in LMNA and could be a possible therapeutic target in the future.
Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure
Keywords: Arrhythmias, Cardiac, Atrial Fibrillation, Bradycardia, Cardiomyopathies, Cardiomyopathy, Dilated, Genetics, Population, Heart Failure, Loss of Function Mutation, Middle Aged, Mutation, Missense, Risk, Secondary Prevention, Whole Exome Sequencing
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