A recent study shows that uncommon genetic mutations greatly elevate the risk of atrial fibrillation

A groundbreaking genetic study has unveiled significant findings regarding the risk factors associated with atrial fibrillation (AF), a common heart rhythm disorder. Conducted using data from the UK Biobank, the study focused on the role of both rare and common genetic variants in AF development.

Researchers identified rare genetic variants in six specific genes—TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71—that are predicted to cause loss of function. These variants were strongly associated with an increased risk of developing AF. Notably, the study highlighted that these rare variants, when combined with a polygenic risk score (PRS) for AF, significantly elevated the likelihood of incident AF.

The study, which included over 400,000 individuals of European ancestry aged 40-69 years, excluded those with prior AF diagnoses. Over a median follow-up period of 13.3 years, 24,447 individuals were diagnosed with incident AF. Beyond AF, the rare genetic variants also demonstrated associations with heightened risks of cardiomyopathy (CM) and heart failure (HF), both before and after the onset of AF. This underscores the broader implications of genetic testing in predicting and managing cardiovascular diseases.

 

AF, the most prevalent form of cardiac arrhythmia, can manifest as either paroxysmal (lasting less than seven days) or persistent (lasting more than seven days). Estimates suggest that the incidence of AF could double or triple by 2050. While AF affects approximately 1% of the global population, its prevalence rises to around 9% among those aged 75 and older. By the age of 80, the lifetime risk of developing AF increases to 22%. Furthermore, this condition has been more frequently observed in males and is more prevalent among individuals of white ethnicity compared to those of black ethnicity.

 

Genome-wide association studies have identified over a hundred single nucleotide polymorphisms associated with AF risk. Additional sources of AF heritability may stem from promoter variants, epigenetic factors, structural variants, and other as-yet undiscovered genetic mechanisms. Andersen et al. reported that genetic variations in genes responsible for ion channels, transcription factors, and structural components of the myocardium predispose individuals to AF by influencing pathways that increase automaticity and promote re-entry activity.

 

The current findings represent a pivotal step forward in understanding the genetic underpinnings of AF. They suggest that assessing both rare and common genetic variations could revolutionize AF prevention and treatment strategies, potentially leading to more personalized approaches in cardiovascular care. This research lays the groundwork for future studies aimed at refining genetic risk assessments and developing targeted interventions to mitigate the impact of AF and related cardiovascular complications.

 

Reference

  1. Rare and Common Genetic Variation Underlying Atrial Fibrillation Risk | Genetics and Genomics | JAMA Cardiology | JAMA Network [Internet]. [cited 2024 Jul 2]. Available from: https://jamanetwork.com/journals/jamacardiology/fullarticle/2820520
  2. Nesheiwat Z, Goyal A, Jagtap M. Atrial Fibrillation. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Jul 2]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK526072/
  3. Peters SAE, Woodward M. Established and novel risk factors for atrial fibrillation in women compared with men. Heart. 2019 Feb;105(3):226–34.
  4. Andersen JH, Andreasen L, Olesen MS. Atrial fibrillation—a complex polygenetic disease. Eur J Hum Genet. 2021 Jul;29(7):1051–60.
  5. Temporal trends of the prevalence and incidence of atrial fibrillation and stroke among Asian patients with hypertrophic cardiomyopathy: A nationwide population-based study – PubMed [Internet]. [cited 2024 Jul 2]. Available from: https://pubmed.ncbi.nlm.nih.gov/30150122/

 

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