RESUMO
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.
Assuntos
Morte Súbita Cardíaca/etiologia , Mutação INDEL , Polimorfismo Genético , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adolescente , Adulto , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Adulto JovemRESUMO
Fifty-six sudden unexplained death (SUD) cases were collected from Chinese Han population, which occurred during daily activities and were autopsy negative in comprehensive postmortem autopsy. The coding exons of potassium channel genes KCNE1, KCNQ1, and nitric oxide synthase gene NOS1AP were sequenced. A synonymous mutation, KCNE1 F54F T>C was identified in 2 SUD cases, which was absent in the control subjects. Neither genotype nor allele frequencies of KCNE1 and KCNQ1 exhibited a significant difference between the SUD and control group. In contrast, the allele frequency (p = 2.7 × 10(-10)) and genotype frequency (p = 5.9 × 10(-7)) of rs3751284, and the genotype frequency (p = 2.9 × 10(-2)) of rs348624 in NOS1AP of SUD were significantly different from that of controls (p < 0.05). Our study suggested that rs3751284 and rs348624 might be susceptibility loci for SUD during daily activities. Larger sample sizes and further molecular studies are needed to confirm or exclude an effect of the NOS1AP SNPs on SUD risk.
Assuntos
Atividades Cotidianas , Proteínas Adaptadoras de Transdução de Sinal/genética , Morte Súbita/etiologia , Canal de Potássio KCNQ1/genética , Polimorfismo de Nucleotídeo Único , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Adulto , Estudos de Casos e Controles , China/etnologia , Morte Súbita/etnologia , Éxons , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Mutação , Análise de SequênciaRESUMO
OBJECTIVE: To investigate the single nucleotide polymorphism of NOS1AP gene with sudden unexpected death (SUD) during daily activities. METHODS: The heart blood samples were collected from 60 SUD cases in normal daily activities as SUD group and the peripheral blood samples from 80 random unrelated cases as control group. The genome DNAs from all cases were isolated and the gene sequences were analyzed from specific primers of some SNP (rs10494366, rs10918859, rs12143842, rs12742393, rs3751284, and rs348624) of NOS1AP. The allele frequency and genotype frequency were calculated and the difference in these SNP between SUD group and control group were analyzed. RESULTS: The allele frequency and genotype frequency of rs3751284 which located at the sixth exon domain had significant statistical differences between the two groups (P<0.05). The minor allele frequency of rs3751284 was 0.325 in SUD group and was 0.475 in control group. CONCLUSION: rs3751284 might be a susceptibility locus for SUD.
