| Atrial fibrillation (AF) is an abnormal heart rhythm characterized by rapid and irregular beating at a rate of350-600bpm. Atrial fibrillation (AF) is the most common cardiac arrhythmia in general population and in patients after cardiac sugery. Epidemiologic data showed that the prevalence rate of AF was about1%in caucasians and0.77%in Chinese in general population, and as high as8%in elders greater than80years. What is more, AF can increase5folds of risk of stroke,3folds to heart failure, and about2.14-3.26folds to sudden cardiac death. AF is one of most important issue to human health.The mechanism of AF is uncertain. Inflammation may play an important role in process of pathology of AF, however, inflammation is the cause or the consequence of atrail fibrillation and which specific inflammatory mediators may increase the atria’s susceptibility to fibrillation remain elusive. In previous study in animal model, Myeloperoxidase (MPO), which is a leukocyte-derived heme enzyme, by generating hypochlorous acid (HOC1), is a crucial regulator switch modulating MMP activity, and strongly linked to the inflammation process of remodeling in atria. MPO-deficient mice pretreated with angiotensin Ⅱ (AngⅡ) to provoke leukocyte activation showed lower atrial tissue abundance of the MPO product3-chlorotyrosine, reduced activity of matrix metalloproteinases and blunted atrial fibrosis as compared to wild-type mice. Upon right atrial electrophysiological stimulation, MPO-deficient mice were protected from atrial fibrillation, which was reversed when MPO was restored. What is more, patients with atrial fibrillation had higher plasma concentrations of MPO and a larger MPO burden in right atrial tissue as compared to individuals free of atrial fibrillation. However, the genetic evidence of the association between MPO and the risk of AF in human population was lack.In animal model, Myeloperoxidase (MPO) was showed as a crucial regulator to the inflammation process of remodeling in atrial, however, the genetic evidence of the association between MPO and AF in human population was lack. In this study, we assess the association between rs2243828, a variant in promoter region of MPO and the risk of AF in two independent case control cohorts with a total of1,800AF cases and2,211controls from a Chinese GeneID population., The results demonstrated that G allele of rs2243828showed a significant protective effect to AF in both discover cohort (694cases and710controls, observed P-obs=7.65×10-3, adjusted P-adj=6.25×10-3with an odds ratio was0.77) and replication cohort (1,106cases and1,501controls, P-obs=7.28×10-5, P-adj=9.88×10-5with an odds ratio was0.75). The results also showed G allele was significantly associated with lower plasma MPO concentration under a dominant model with a P was1.16×10-4. We also observed a significant difference of odds ratio between sub-groups of hypertension and non-hypertension (P=3.11×10-4). Our study first identified variant in MPO as a novel genetic risk factor to AF, and give strong evidences to link the inflammation as a causal agent of incidence of AF.In summary, we carried out a candidate case control association study for AF in two independent Chinese Han population, and identified a novel association between variant of MPO gene an AF. We provided strong genetic evidence to demonstrate that SNP rs2243828in MPO gene, which associated with plasma MPO level, associated with AF risk in Chinese Han GeneID population. These results show that the inflammation may confer risk in the pathogenesis of AF. Therefore, restriction of inflammation may be a potential scheme for the prevention and treatment of AF. |
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