*For information only by medical professionals
The LMNA gene encodes lamin A, which is expressed in differentiated somatic cells. Lamin A/C provides structural support to the nucleus and mediates chromatin organization and gene expression among other functions.
Due to the pleiotropy of lamin A/C, dysfunctional variants of this gene cause a heterogeneous group of diseases collectively known as laminopathies. Rare genetic variants in LMNA are known to cause dilated cardiomyopathy alone or in conjunction with conduction defects, and in some cases the only manifestations are conduction delays, atrial arrhythmias, or ventricular arrhythmias . However, many rare LMNA gene variants exist in the general population, and their role in cardiovascular disease has not yet been determined.
Large-scale genetic sequencing of population-based biobanks has made it possible to explore the natural history of genetic variants and how they contribute to disease susceptibility.
Recently, JACC magazine published a study using data from the UK Biobank to study the impact of rare loss-of-function and missense LMNA variants on arrhythmia and cardiomyopathy susceptibility. Let’s take a look.
Research Methods
Whole-exome sequencing was performed on 185,990 UK Biobank participants.
annotated the functional effects of rare loss-of-function and missense LMNA variants using 30 in silico prediction tools.
assigned a predicted functional effect weight to each variant and calculated the score of the vector.
evaluated the association between LMNA scores and arrhythmia (atrial fibrillation, bradyarrhythmias, ventricular arrhythmias) or cardiomyopathy outcomes (dilated cardiomyopathy and heart failure ).
investigated the correlation of variants located upstream and downstream of the nuclear localization signal.
Study Results
Overall,
1167 (0.63%) participants carried the LMNA variant, and
15079 (8.11%) participants experienced an arrhythmic or cardiomyopathic event during a median follow-up of 10.9 years.
LMNA score was associated with arrhythmia or cardiomyopathy (OR 2.21; P0.001), and the association was more significant when
was restricted to variants upstream of the nuclear localization signal (OR 5.05; P0.001).
Incidence of arrhythmia or cardiomyopathy: 8.43/1000 person-years for
LMNA variant carriers (95% confidence interval: 6.73-10.12/1000 person-years) and 6.38/1000 person-years for
non-carriers (95% confidence interval: 6.73-10.12/1000 person-years) Confidence interval: 6.27-6.50/1000 person-years).
Only 3 (1.2%) variants were reported as pathogenic in ClinVar.
Study Conclusions
Middle-aged adults with rare missense or loss-of-function LMNA variants are at increased risk for arrhythmias and cardiomyopathy.
Source:
LMNA Variants and Risk of Adult-Onset Cardiac Disease. J Am Coll Cardiol 2022;80:50–59. doi: 10.1016/j.jacc.2022.04.035
