EDITORIAL COMMENTARY
Sequencing deeper to find the genetic mechanism of atrial fibrillation Arnold Edward Pfahnl, MD, PhD, FHRS From the Banner Health Cardiovascular Institute of North Colorado, Greeley, Colorado. The principle of inheritance as originally described by Gregor Mendel through his pea experiments in the 1860s laid the foundation for modern genome-wide association studies (GWAS). Although Mendelian genetics allowed the identification of the first genetic diseases such as cystic fibrosis and Duchene muscular dystrophy, “Mendelian” diseases are rare. Many common diseases, such as atrial fibrillation, are inheritable, but have multifaceted genetic components that cannot be determined using Mendelian genetics. The human genome project, completed 10 years ago, made GWAS possible by allowing the identification of specific areas in the human genome that contain variability, which include single nucleotide polymorphisms (SNPs). GWAS scan for markers in the human genome of many individuals to find genetic variations associated with a disease, specifically atrial fibrillation in the article by Lin et al in this issue of HeartRhythm.1 To further illustrate how GWAS works, take a variable, such as an SNP or in an epidemiological study, sleep apnea, and seek an association with familial atrial fibrillation risk. Since 2005, GWAS has resulted in more than 200 associations with complex diseases. Some of the benefits of GWAS include the identification of biomarkers, disease risk prediction, subclassifying diseases, and tailoring drug treatment, for example, chemotherapy.2 GWAS have limitations, however. For example, previous studies assessing the risk factors for new-onset familial atrial fibrillation determined that common genetic variants were not an independent risk factor, suggesting causal variants may be less common.2 That is, most SNPs that have been identified are not the causal variants but are indirectly associated with the disease of interest, and they are often great distances from the protein-coding genes, making it challenging to find the causal variants.2 The challenge, as the present article in this issue of HeartRhythm illustrates, to find the rarer causal variants involves sequencing much more DNA. An even more complex challenge is to assess the environmental effects on genetic variants. GWAS have identified 9 genetic loci related to atrial fibrillation, with the authors focusing their efforts on 4 of these.3 Given the immensity of the human genome and limited Address reprint requests and correspondence: Dr Arnold Edward Pfahnl, Banner Health Cardiovascular Institute of North Colorado, 1800 15th St, Suite 310, Greeley, CO 80631. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
resources, at present it is not feasible to sequence the entire human genome of more than a thousand humans to detect associations. In order to undertake this targeted but large effort, the authors combined forces with a larger consortium to sequence 77 target genes in more than 900 patients with atrial fibrillation and more than 300 controls.1 The 77 genes were chosen on the basis of their associated phenotypes, with 4 genes specifically selected for their association with atrial fibrillation. The results revealed 1 common SNP and 1 gene region, with a significant association with atrial fibrillation. The common SNP identified in the present article is located in the first intron of interleukin-6 receptor. The association of atrial fibrillation with the interleukin-6 receptor is reasonable because it plays a role in inflammation and thus may have direct effects on atrial fibrillation promotion.4 The gene region identified, PRRX1, plays a role in regulating muscle creatine kinase, whereby it controls growth and development in mesodermal muscle such as the heart.5 In addition, PRRX1 has been shown to be expressed in human cardiomyocytes and specifically in mouse cardiac atrial tissue.5 The results lay the groundwork for future studies that will ultimately map protein-encoding genes that play a direct role in atrial fibrillation mechanisms and uncover the complex genetic background of atrial fibrillation. In addition, with new sequencing devices such as those from Illumina that recently received the approval of the Food and Drug Administration,6 we will soon have the ability to sequence deeper and faster to uncover the mechanism for atrial fibrillation.
References 1. Lin H, Sinner MF, Brody JA, et al. Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study. Heart Rhythm 2014;11:452–457. 2. Manolio TA. Bringing genome-wide association findings into clinical use. Nat Rev Genet 2013;14:549–558. 3. Ellinor PT, Lunetta KL, Albert CM, et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet 2012;44:670–675. 4. Ferreira RC, Freitag DF, Cutler AJ, et al. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS Genet 2013;9:e1003444. 5. Paired related homeobox 1. GeneCards.org Web site.http://www.genecards.org/ cgi-bin/carddisp.pl?gene=PRRX1. Accessed December 2, 2013. 6. Collins FS, Hamburg MA. First FDA authorization for next-generation sequencer. N Engl J Med 2013;369:2369–2371. Nature 2013; http://dx.doi.org/10.1056/ NEJMp1314561.
http://dx.doi.org/10.1016/j.hrthm.2013.12.005
Sequencing deeper to find the genetic mechanism of atrial fibrillation Arnold Edward Pfahnl, MD, PhD, FHRS From the Banner Health Cardiovascular Institute of North Colorado, Greeley, Colorado. The principle of inheritance as originally described by Gregor Mendel through his pea experiments in the 1860s laid the foundation for modern genome-wide association studies (GWAS). Although Mendelian genetics allowed the identification of the first genetic diseases such as cystic fibrosis and Duchene muscular dystrophy, “Mendelian” diseases are rare. Many common diseases, such as atrial fibrillation, are inheritable, but have multifaceted genetic components that cannot be determined using Mendelian genetics. The human genome project, completed 10 years ago, made GWAS possible by allowing the identification of specific areas in the human genome that contain variability, which include single nucleotide polymorphisms (SNPs). GWAS scan for markers in the human genome of many individuals to find genetic variations associated with a disease, specifically atrial fibrillation in the article by Lin et al in this issue of HeartRhythm.1 To further illustrate how GWAS works, take a variable, such as an SNP or in an epidemiological study, sleep apnea, and seek an association with familial atrial fibrillation risk. Since 2005, GWAS has resulted in more than 200 associations with complex diseases. Some of the benefits of GWAS include the identification of biomarkers, disease risk prediction, subclassifying diseases, and tailoring drug treatment, for example, chemotherapy.2 GWAS have limitations, however. For example, previous studies assessing the risk factors for new-onset familial atrial fibrillation determined that common genetic variants were not an independent risk factor, suggesting causal variants may be less common.2 That is, most SNPs that have been identified are not the causal variants but are indirectly associated with the disease of interest, and they are often great distances from the protein-coding genes, making it challenging to find the causal variants.2 The challenge, as the present article in this issue of HeartRhythm illustrates, to find the rarer causal variants involves sequencing much more DNA. An even more complex challenge is to assess the environmental effects on genetic variants. GWAS have identified 9 genetic loci related to atrial fibrillation, with the authors focusing their efforts on 4 of these.3 Given the immensity of the human genome and limited Address reprint requests and correspondence: Dr Arnold Edward Pfahnl, Banner Health Cardiovascular Institute of North Colorado, 1800 15th St, Suite 310, Greeley, CO 80631. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
resources, at present it is not feasible to sequence the entire human genome of more than a thousand humans to detect associations. In order to undertake this targeted but large effort, the authors combined forces with a larger consortium to sequence 77 target genes in more than 900 patients with atrial fibrillation and more than 300 controls.1 The 77 genes were chosen on the basis of their associated phenotypes, with 4 genes specifically selected for their association with atrial fibrillation. The results revealed 1 common SNP and 1 gene region, with a significant association with atrial fibrillation. The common SNP identified in the present article is located in the first intron of interleukin-6 receptor. The association of atrial fibrillation with the interleukin-6 receptor is reasonable because it plays a role in inflammation and thus may have direct effects on atrial fibrillation promotion.4 The gene region identified, PRRX1, plays a role in regulating muscle creatine kinase, whereby it controls growth and development in mesodermal muscle such as the heart.5 In addition, PRRX1 has been shown to be expressed in human cardiomyocytes and specifically in mouse cardiac atrial tissue.5 The results lay the groundwork for future studies that will ultimately map protein-encoding genes that play a direct role in atrial fibrillation mechanisms and uncover the complex genetic background of atrial fibrillation. In addition, with new sequencing devices such as those from Illumina that recently received the approval of the Food and Drug Administration,6 we will soon have the ability to sequence deeper and faster to uncover the mechanism for atrial fibrillation.
References 1. Lin H, Sinner MF, Brody JA, et al. Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study. Heart Rhythm 2014;11:452–457. 2. Manolio TA. Bringing genome-wide association findings into clinical use. Nat Rev Genet 2013;14:549–558. 3. Ellinor PT, Lunetta KL, Albert CM, et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet 2012;44:670–675. 4. Ferreira RC, Freitag DF, Cutler AJ, et al. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS Genet 2013;9:e1003444. 5. Paired related homeobox 1. GeneCards.org Web site.http://www.genecards.org/ cgi-bin/carddisp.pl?gene=PRRX1. Accessed December 2, 2013. 6. Collins FS, Hamburg MA. First FDA authorization for next-generation sequencer. N Engl J Med 2013;369:2369–2371. Nature 2013; http://dx.doi.org/10.1056/ NEJMp1314561.
http://dx.doi.org/10.1016/j.hrthm.2013.12.005
