title: An insertion/deletion polymorphism within 3'UTR of RYR2 modulates sudden unexplained death risk in Chinese populations.
abstract: Sudden unexplained death (SUD) constitutes a part of the overall sudden death that can not be underestimated. Over the last years, genetic testing on SUD has revealed that inherited channelopathies might play important roles in the pathophysiology of this disease. Ryanodine receptor type-2 (RYR2) is a kind of ion channel extensively distributed in the sarcoplasmic reticulum (SR) of myocardium. Studies on RYR2 have suggested that either dysfunction or abnormal expression of it could lead to arrhythmia, which may cause cardiac arrest. In this study, we conducted a case-control study to evaluate the association of a 4-base pair (4-bp) Indel polymorphism (rs10692285) in the 3'UTR of RYR2 with the risk of SUD and sudden cardiac death induced by coronary heart disease (SCD-AS) in a Chinese population. Logistic regression analysis showed that the insertion allele of rs10692285 had significantly increased the risk of SUD [OR=2.03; 95% confidence interval (CI)=1.08-3.77; P=0.0161; statistical power=0.743]. No relevance was observed between rs10692285 and SCD-AS. Further genotype-phenotype association analysis suggested that the expression level of RYR2 in human myocardium tissues with the insertion allele was higher than that with the deletion allele at both mRNA and protein levels. Dual-Luciferase activity assay system was used to detect the effect of rs10692285 on the transcription activity of RYR2. As expected, the result indicated that the transcription activity of RYR2 with the ins/ins genotype was higher than that with the del/del genotype. Finally, in-silico prediction revealed that different alleles of rs10692285 could alter the local structure of RYR2 mRNA and microRNA (miRNA) binding. In summary, our findings provided evidence that rs10692285 might contribute to SUD susceptibility through affecting the expression of RYR2, which suggest that abnormal ion channel activity is very likely to be the underlying mechanism of SUD, but not for SCD-AS. Thus, rs10692285 may become a potential marker for molecular diagnosis and genetic counseling of SUD.
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.
authors.forename: Shouyu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.
authors.forename: Chaoqun
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.
authors.forename: Ruiyang
authors.initials: R
authors.lastname: Tao
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.
authors.forename: Shuxiang
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Epidemiology, Medical College of Soochow University, Suzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Shanghai Key Laboratory of Forensic Medicine, Institute of Forensic Sciences, Ministry of Justice, Shanghai, China.
authors.forename: Chengtao
authors.initials: C
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Forensic Medicine, Institute of Forensic Sciences, Ministry of Justice, Shanghai, China.
authors.forename: Suhua
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Forensic Medicine, Institute of Forensic Sciences, Ministry of Justice, Shanghai, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Public Security Bureau of Shenzhen, Shenzhen, China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Sheng
authors.affiliation: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Fangyu
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address: luobin@mail.sysu.edu.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Luo
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China. Electronic address: yuzhengao@suda.edu.cn.
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002681:China; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D011110:Polymorphism, Genetic; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C000621072:RyR2 protein, human; D019837:Ryanodine Receptor Calcium Release Channel
keywords: Genetic susceptibility; Indel polymorphism; Ryanodine receptor type-2; Sudden unexplained death; rs10692285