• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • The renin angiotensin system plays a


    The renin-angiotensin system plays a crucial role in atrial fibrosis, which is a key pathological consequence of AF. Genes encoding 3 molecules related to the renin-angiotensin system, including angiotensin-converting enzyme (ACE), angiotensinogen, and angiotensin type 1 receptor (AT1R), are associated with AF [21,22]. Electrical coupling is vital to atrial myocytes, and this is provided by intercellular channels termed Cxs. Among these, C×40 (GJA5) is selectively found in the atria and in the His-Purkinje system. Juang et al. found that a GJA5 haplotype (−44A+71G), common to the population was associated with a significantly higher risk for AF [24]. Interestingly, 4 mutations in GJA5 were found in genomic DNA isolated from atrial tissue specimens from patients with lone AF, but these mutations were absent from genomic DNA isolated from the lymphocytes of these patients [25]. These results suggest that in addition to traditional germline mutations, somatic mutations might also play an important role in a predisposition towards AF. AF patients have high sensitive CRP levels [30], and chronic inflammation plays a role in AF pathogenesis. Genes encoding 3 pro-inflammatory cytokines, IL-1β, IL-6, and IL-10, are found to be associated with AF [26–28]. AF is a frequent complication of open-chest surgery. Gaudino et al. found that the −174G/C IL-6 polymorphism determines postoperative levels of IL-6; those with the GG genotype have a higher incidence of AF compared to those without the GG genotype (33.9% vs. 10.4%; hazard ratio, 3.25; 95% CI 1.23–8.62) [28]. The risk for AF development increases with increasing age. A common type of mitochondrial DNA (mtDNA) deletion mutation, a 4977-bp deletion mutation from neuraminidase inhibitors pairs 8470 and 13446 (mtDNA4977) [31], has been used as a general index of somatic mtDNA mutations, and has been reported in various tissues from aging humans [32]. The presence of mtDNA deletion mutations appears to be a risk factor for AF in older populations. Lai et al. found that the relative amount of mtDNA4977 was significantly higher in patients with AF than in patients without AF in older populations, but not in children or adolescents[29].
    What is GWAS About 3–10 million variants are assumed to be present in the entire human genome, which consists of about 30 billion base pairs. As with the genotype, the pattern of variants is termed as the haplotype. Homologous recombination does not occur randomly over the whole genome. Instead, it occurs at the certain sites, referred to as homologous recombination hot spots. The region from one homologous recombination hot spot to the next is called the haplo-block, in which variants rarely exchange (Fig. 1). If variants A and B are present within a single haplo-block, then the presence of variant A indicates a very high probability (usually>90%) of the presence of variant B. In contrast, the absence of variant A indicates a very low likelihood of the presence of variant B. Such variants that show similar transmission characteristics are claimed to be in linkage disequilibrium (LD). Because of the presence of LD, only about 10% of all variants (about 0.3–1.0 million variants) need to be analyzed in order to assess the haplotype of the entire genome. Thanks to technological advances, it is possible to analyze up to 1 million variants simultaneously. The analysis of up to 1 million variants in the entire genome (most frequently 610,000 SNPs) is called a GWAS (genome-wide association study), and is widely employed in the study of various common diseases.
    GWAS for AF The result of a GWAS for AF was first reported from the Decode project in 2007 [33]. This study analyzed the association of 316,515 SNPs in 550AF/atrial flutter (AFL) patients and 4,476 controls from Iceland. The researchers found associations between AF/AFL and several SNPs in the 4q25 region. Since then, 2 other loci associated with AF have been identified, one in 1q21 [34] and the other in 16q22[36].