Association between an indel polymorphism in the 3'UTR of COL1A2 and the risk of sudden cardiac death in Chinese populations.

Sudden cardiac death (SCD) describes the unexpected natural death from a cardiac cause within a short time period. Compelling evidence suggests the involvement of host genetic factors in SCD etiology. Identification of genetic variations predisposed to SCD enables genetic testing that may contribute to SCD diagnosis and risk stratification. Previous studies have suggested that dysregulation of pro-alpha2 chain of type I collagen, encoded by collagen type I alpha 2 chain (COL1A2) gene, was involved in cardiac disorders such as myocardial infarction, hypertrophic cardiomyopathy and atherosclerosis. By using a candidate-gene-based approach, we evaluated the association of a 7-base pair (7-bp) indel polymorphism (rs3917) in the 3'UTR of COL1A2 with the risk of SCD in a Chinese population (79SCD cases and 328 controls). Logistic regression analysis showed that the deletion allele of rs3917 significantly increased the risk of SCD [odds ratio (OR)=1.82; 95% confidence interval (CI)=1.08-3.06; P=0.0159]. Further genotype-phenotype association analysis revealed that the deletion allele was markedly correlated with lower expression of COL1A2 in human myocardium tissues. The luciferase activity analysis in an in vitro reporter gene system suggested that rs3917 could regulate COL1A2 expression through interrupting the binding of miR-296-3p with COL1A2 in an allele-dependent manner, which in turn confer SCD risk. Our data provided initial evidence that rs3917 was highly relevant to SCD susceptibility, and this indel may become a potential marker for molecular diagnosis and genetic counseling of SCD. The replication of our studies and further functional studies are needed to validate our findings.

Influence of functional polymorphism in MIF promoter on sudden cardiac death in Chinese populations.

Sudden cardiac death (SCD) is defined as an unexpected natural death without any obvious non-cardiac causes that occurs within 1 h with witnessed symptom onset or within 24 h without witnessed symptom onset. Genetic studies conducted during the past decade have markedly illuminated the genetic basis of the cardiac disorders associated with SCD. Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory cytokine associated with the pathogenesis of many inflammatory diseases including atherosclerosis and myocardial infarction. Previous studies have reported that the functional -794(CATT)5-8 polymorphism in MIF is unrelated to sudden infant death syndrome susceptibility. However, there are no reports concerning the association between the polymorphism and adult SCD susceptibility. In the current study, we investigated the association between the -794(CATT)5-8 polymorphism and adult SCD susceptibility using 79 adult SCD cases and 313 healthy controls. All samples were analysed using a conventional polymerase chain reaction (PCR) technique. We found that CATT6 and 5-6 were the most common allele and genotype in both groups, respectively, while no significant association was found between the -794(CATT)5-8 polymorphism and SCD susceptibility. We also summarized the allele frequencies of -794(CATT)5-8 in cohorts of healthy people from different countries and found that the allele frequency distributions of the polymorphism in Chinese populations were quite different from that of American and European populations (P = 0.005, P = 0.0001, respectively), but similar to Japanese populations (P = 0.827). In conclusion, this study indicates that the -794(CATT)5-8 polymorphism may not be associated with adult SCD susceptibility in Chinese populations. Different allele frequency distributions of the polymorphism in multiple populations may provide a useful reference for further genetic association studies.

An insertion/deletion polymorphism within 3'UTR of RYR2 modulates sudden unexplained death risk in Chinese populations.

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.

An indel polymorphism within pre-miR3131 confers risk for hepatocellular carcinoma.

Polymorphisms in pre-miRNAs may affect its expression, then have effect on its target mRNAs and be associated with cancer susceptibility. In this study, we evaluated the association of an indel polymorphism rs57408770 in pre-miR-3131 with hepatocellular carcinoma (HCC) susceptibility in a Chinese population. The contribution of rs57408770 to HCC risk was investigated in two independent case-control sets (1051 HCC and 1058 controls). Logistic regression analysis showed that the insertion allele of rs57408770 was significantly associated with an increased risk for HCC occurrence in both case-control studies. Moreover, the results of genotype-phenotype correlation analysis from both in vivo and in vitro experiments showed that the insertion allele was significantly correlated with higher expression of mature miR-3131 comparing with the deletion allele. The RNA-Binding Protein Immunoprecipitation assay results indicated that rs57408770 could affect the expression level of mature miR-3131 probably through disturbing the binding of splicing factor SRp20 with pre-miR-3131. Furthermore, overexpression of miR-3131 displayed a proliferation promoting and anti-apoptosis effect on HCC cell lines, suggesting that miR-3131 may act as a proto-oncogene in HCC. Finally, human genome-wide gene expression profile assay was used to screen the targets of miR-3131. The overexpressed miR-3131 could lead to a significant decrease of DTHD1 and XAF1 mRNA level. Taken together, our findings provided evidence that rs57408770 may play a functional role in the carcinogenesis of HCC by affecting SRp20 binding with pre-miR-3131 and affecting the expression of mature miR-3131, subsequently affecting the expression of DTHD1 and XAF1, thus confers risk for HCC.