Genetics of atrial fibrillation: rare mutations, common polymorphisms, and clinical relevance.
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ABSTRACT:
SUBMITTER: Darbar D
PROVIDER: S-EPMC2292402 | biostudies-literature | 2008 Mar
REPOSITORIES: biostudies-literature
Publications
Genetics of atrial fibrillation: rare mutations, common polymorphisms, and clinical relevance.
Heart rhythm 20070918 3
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Project description:Atrial fibrillation (AF) is the most common heart rhythm disorder worldwide and may have serious cardiovascular health consequences. AF is associated with increased risk of stroke, dementia, heart failure, and death. There are several known robust, clinical risk predictors for AF, such as male sex, increasing age, and hypertension; however, during the last couple of decades, a substantive genetic component has also been established. Over the last 10 years, the discovery of novel AF-related genetic variants has accelerated, increasing our understanding of mechanisms behind AF. Current studies are focusing on mapping the polygenic structure of AF, improving risk prediction, therapeutic development, and patient-specific management. Nevertheless, it is still difficult for clinicians to interpret the role of genetics in AF prediction and management. Here, we provide an overview of relevant topics within the genetics of AF and attempt to provide some guidance on how to interpret genetic advances and their implementation into clinical decision-making.
| S-EPMC6743416 | biostudies-literature
Project description:ImportanceAtrial fibrillation (AF) has a substantial genetic component. The importance of polygenic risk is well established, while the contribution of rare variants to disease risk warrants characterization in large cohorts.ObjectiveTo identify rare predicted loss-of-function (pLOF) variants associated with AF and elucidate their role in risk of AF, cardiomyopathy (CM), and heart failure (HF) in combination with a polygenic risk score (PRS).Design, setting, and participantsThis was a genetic association and nested case-control study. The impact of rare pLOF variants was evaluated on the risk of incident AF. HF and CM were assessed in cause-specific Cox regressions. End of follow-up was July 1, 2022. Data were analyzed from January to October 2023. The UK Biobank enrolled 502 480 individuals aged 40 to 69 years at inclusion in the United Kingdom between March 13, 2006, and October 1, 2010. UK residents of European ancestry were included. Individuals with prior diagnosis of AF were excluded from analyses of incident AF.ExposuresRare pLOF variants and an AF PRS.Main outcomes and measuresRisk of AF and incident HF or CM prior to and subsequent to AF diagnosis.ResultsA total of 403 990 individuals (218 489 [54.1%] female) with a median (IQR) age of 58 (51-63) years were included; 24 447 were diagnosed with incident AF over a median (IQR) follow-up period of 13.3 (12.4-14.0) years. Rare pLOF variants in 6 genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) were associated with AF. Of these, TTN, RPL3L, PKP2, CTNNA3, and KDM5B replicated in an external cohort. Combined with high PRS, rare pLOF variants conferred an odds ratio of 7.08 (95% CI, 6.03-8.28) for AF. Carriers with high PRS also had a substantial 10-year risk of AF (16% in female individuals and 24% in male individuals older than 60 years). Rare pLOF variants were associated with increased risk of CM both prior to AF (hazard ratio [HR], 3.13; 95% CI, 2.24-4.36) and subsequent to AF (HR, 2.98; 95% CI, 1.89-4.69).Conclusions and relevanceRare and common genetic variation were associated with an increased risk of AF. The findings provide insights into the genetic underpinnings of AF and may aid in future genetic risk stratification.
| S-EPMC11209175 | biostudies-literature
Project description:Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting 1-2% of the general population. A number of studies have demonstrated that AF, and in particular lone AF, has a substantial genetic component. Monogenic mutations in lone and familial AF, although rare, have been recognized for many years. Presently, mutations in 25 genes have been associated with AF. However, the complexity of monogenic AF is illustrated by the recent finding that both gain- and loss-of-function mutations in the same gene can cause AF. Genome-wide association studies (GWAS) have indicated that common single-nucleotide polymorphisms (SNPs) have a role in the development of AF. Following the first GWAS discovering the association between PITX2 and AF, several new GWAS reports have identified SNPs associated with susceptibility of AF. To date, nine SNPs have been associated with AF. The exact biological pathways involving these SNPs and the development of AF are now starting to be elucidated. Since the first GWAS, the number of papers concerning the genetic basis of AF has increased drastically and the majority of these papers are for the first time included in a review. In this review, we discuss the genetic basis of AF and the role of both common and rare genetic variants in the susceptibility of developing AF. Furthermore, all rare variants reported to be associated with AF were systematically searched for in the Exome Sequencing Project Exome Variant Server.
| S-EPMC3925267 | biostudies-literature
Project description:Background Atrial fibrillation ( AF ) is a common arrhythmia seen in clinical practice. Occasionally, no common risk factors are present in patients with this arrhythmia. This suggests the potential underlying role of genetic factors associated with predisposition to developing AF . Methods and Results We conducted a comprehensive review of the literature through large online libraries, including PubMed. Many different potassium and sodium channel mutations have been discussed in their relation to AF . There have also been non-ion channel mutations that have been linked to AF . Genome-wide association studies have helped in identifying potential links between single-nucleotide polymorphisms and AF . Ancestry studies have also highlighted a role of genetics in AF . Blacks with a higher percentage of European ancestry are at higher risk of developing AF . The emerging field of ablatogenomics involves the use of genetic profiles in their relation to recurrence of AF after catheter ablation. Conclusions The evidence for the underlying role of genetics in AF continues to expand. Ultimately, the role of genetics in risk stratification of AF and its recurrence is of significant interest. No established risk scores that are useful in clinical practice are present to date.
| S-EPMC6474960 | biostudies-literature
Project description:Recent studies of atrial fibrillation (AF) have identified mutations in a series of ion channels; however, these mutations appear to be relatively rare causes of AF. A genome-wide association study has identified novel variants on chromosome 4 associated with AF, although the mechanism of action for these variants remains unknown. Ultimately, a greater understanding of the genetics of AF should yield insights into novel pathways, therapeutic targets, and diagnostic testing for this common arrhythmia.
| S-EPMC3073057 | biostudies-literature
Project description:Recent studies of AF have identified mutations in a series of ion channels; however, these mutations appear to be relatively rare causes of AF. A genome-wide association study has identified novel variants on chromosome 4 associated with AF, although the mechanism of action for these variants remains unknown. Ultimately, a greater understanding of the genetics of AF should yield insights into novel pathways, therapeutic targets, and diagnostic testing for this common arrhythmia.
| S-EPMC2675914 | biostudies-literature
Project description:Recent studies of atrial fibrillation (AF) have identified mutations in a series of ion mutations; however, these channels appear to be relatively rare causes of AF. Recent genome-wide association studies for AF have identified novel variants associated with the disease, although the mechanism of action for these variants remains unknown. Ultimately, a greater understanding of the genetics of AF should yield insights into novel pathways, therapeutic targets, and diagnostic testing for this common arrhythmia.
| S-EPMC2905167 | biostudies-literature
Project description:Purpose of reviewAtrial fibrillation is the most common sustained cardiac arrhythmia. In addition to traditional risk factors, it is increasingly recognized that a genetic component underlies atrial fibrillation development. This review aims to provide an overview of the genetic cause of atrial fibrillation and clinical applications, with a focus on recent developments.Recent findingsGenome-wide association studies have now identified around 140 genetic loci associated with atrial fibrillation. Studies into the effects of several loci and their tentative gene targets have identified novel pathways associated with atrial fibrillation development. However, further validations of causality are still needed for many implicated genes. Genetic variants at identified loci also help predict individual atrial fibrillation risk and response to different therapies.SummaryContinued advances in the field of genetics and molecular biology have led to significant insight into the genetic underpinnings of atrial fibrillation. Potential clinical applications of these studies include the identification of new therapeutic targets and development of genetic risk scores to optimize management of this common cardiac arrhythmia.
| S-EPMC8211390 | biostudies-literature
Project description:BackgroundGenome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in SCN10A, encoding the voltage-gated Nav1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in SCN10A, rs6795970 (V1073A, r(2)=0.933). We therefore sought to determine whether common and rare SCN10A variants are associated with early onset AF.Methods and resultsSCN10A was sequenced in 225 AF patients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 single nucleotide polymorphism variant, we included 515 AF patients and 2 control cohorts of 730 individuals free of AF and 6161 randomly sampled individuals. Functional characterization of SCN10A variants was performed by whole-cell patch-clamping. In the lone AF cohort, 9 rare missense variants and 1 splice site donor variant were detected. Interestingly, AF patients were found to have higher G allele frequency of rs6795970, which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio =1.35 [1.16-1.54]; P=2.3×10(-5)). Both of the common variants, A1073 and P1092, induced a gain-of-channel function, whereas the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function.ConclusionsThe common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have effect on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF.
| S-EPMC4392342 | biostudies-literature
Project description:Susceptibility to atrial fibrillation (AF) is determined by well-recognized risk factors such as diabetes mellitus or hypertension, emerging risk factors such as sleep apnea or inflammation, and increasingly well-defined genetic variants. As discussed in detail in a companion article in this series, studies in families and in large populations have identified multiple genetic loci, specific genes, and specific variants increasing susceptibility to AF. Since it is becoming increasingly inexpensive to obtain genotype data and indeed whole genome sequence data, the question then becomes to define whether using emerging new genetics knowledge can improve care for patients both before and after development of AF. Examples of improvements in care could include identifying patients at increased risk for AF (and thus deploying increased surveillance or even low-risk preventive therapies should these be available), identifying patient subsets in whom specific therapies are likely to be effective or ineffective or in whom the driving biology could motivate the development of new mechanism-based therapies or identifying an underlying susceptibility to comorbid cardiovascular disease. While current guidelines for the care of patients with AF do not recommend routine genetic testing, this rapidly increasing knowledge base suggests that testing may now or soon have a place in the management of select patients. The opportunity is to generate, validate, and deploy clinical predictors (including family history) of AF risk, to assess the utility of incorporating genomic variants into those predictors, and to identify and validate interventions such as wearable or implantable device-based monitoring ultimately to intervene in patients with AF before they present with catastrophic complications like heart failure or stroke.
| S-EPMC8436048 | biostudies-literature