Background and Purpose ANRIL has long been considered as the strongest candidate gene at the 9p21 locus, robustly associated with stroke and coronary artery disease (CAD). However, the underlying molecular mechanism remains unknown. The present study works to elucidate such a mechanism. Methods Utilizing eQTL analysis we identified potential genes whose expression may be influenced by genetic variation in ANRIL. To verify the identified gene(s), knockdown and over-expression of ANRIL was evaluated in HUVECs and HepG2 cells. Ischemic stroke and CAD risk was then evaluated in the gene(s) demonstrated to be mediated by ANRIL in 3 populations of Chinese Han ancestry; two ischemic stroke populations including the Central China cohort (903 cases and 873 controls) and the Northern China cohort (816 cases and 879 controls), and one CAD cohort consisting of 772 patients and 873 controls. Results eQTL analysis identified CARD8 among others, with knockdown of ANRIL expression decreasing CARD8 expression and over-expression of ANRIL increasing CARD8 expression. The minor T allele of a previously identified CARD8 variant (rs2043211) was found to be significantly associated with a protective effect of ischemic stroke under the recessive model in two independent stroke cohorts. No significant association was found between rs2043211 and CAD. Conclusion CARD8 is a downstream target gene regulated by ANRIL. SNP rs2043211 in CARD8 is significantly associated with ischemic stroke. ANRIL may increase the risk of ischemic stroke through regulation of the CARD8 pathway.

In type 1 and type 2 diabetes mellitus, increased cardiac fibrosis, stiffness and associated diastolic dysfunction may be the earliest pathological phenomena in diabetic cardiomyopathy. Endothelial‐mesenchymal transition (EndMT) in endothelia cells (ECs) is a critical cellular phenomenon that increases cardiac fibroblasts (CFs) and cardiac fibrosis in diabetic hearts. The purpose of this paper is to explore the molecular mechanism of miR‐21 regulating EndMT and cardiac perivascular fibrosis in diabetic cardiomyopathy. In vivo, hyperglycaemia up‐regulated the mRNA level of miR‐21, aggravated cardiac dysfunction and collagen deposition. The condition was recovered by inhibition of miR‐21 following with improving cardiac function and decreasing collagen deposition. miR‐21 inhibition decreased cardiac perivascular fibrosis by suppressing EndMT and up‐regulating SMAD7 whereas activating p‐SMAD2 and p‐SMAD3. In vitro, high glucose (HG) up‐regulated miR‐21 and induced EndMT in ECs, which was decreased by inhibition of miR‐21. A highly conserved binding site of NF‐κB located in miR‐21 5′‐UTR was identified. In ECs, SMAD7 is directly regulated by miR‐21. In conclusion, the pathway of NF‐κB/miR‐21/SMAD7 regulated the process of EndMT in T1DM, in diabetic cardiomyopathy, which may be regarded as a potential clinical therapeutic target for cardiac perivascular fibrosis.

The interleukin 1 family plays an important role in the immune and inflammatory responses. Coronary artery disease (CAD) is a chronic inflammatory disease. However, the genetic association between IL-37, the seventh member of the IL-1 family, and CAD is unknown. Here we show that a single nucleotide polymorphism in the IL-37 gene (rs3811047) confers a significant risk of CAD. We have performed an association analysis between rs3811047 and CAD in two independent populations with 2,501 patients and 3,116 controls from China. Quantitative RT-PCR analysis has been performed to determine if the IL-37 expression level is influenced by rs3811047. We show that the minor allele A of rs3811047 is significantly associated with CAD in two independent populations under a recessive model (Padj = 5.51 × 10−3/OR = 1.56 in the GeneID Northernern population and Padj = 1.23 × 10−3/OR = 1.45 in the GeneID Central population). The association became more significant in the combined population (Padj = 9.70 × 10−6/OR = 1.47). Moreover, the association remains significant in a CAD case control population matched for age and sex. Allele A of rs3811047 shows significant association with a decreased mRNA expression level of IL-37 (n = 168, P = 3.78 × 10−4). These data suggest that IL37 is a new susceptibility gene for CAD, which provides a potential target for the prevention and treatment of CAD.

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BackgroundIdiopathic ventricular tachycardia (VT) is a type of cardiac arrhythmia occurring in structurally normal hearts. The heritability of idiopathic VT remains to be clarified, and numerous genetic factors responsible for development of idiopathic VT are as yet unclear. Variations in FGF12 (fibroblast growth factor 12), which is expressed in the human ventricle and modulates the cardiac Na+ channel NaV1.5, may play an important role in the genetic pathogenesis of VT.Methods and ResultsWe tested the hypothesis that genetic variations in FGF12 are associated with VT in 2 independent Chinese cohorts and resequenced all the exons and exon–intron boundaries and the 5′ and 3′ untranslated regions of FGF12 in 320 unrelated participants with idiopathic VT. For population‐based case–control association studies, we chose 3 single‐nucleotide polymorphisms—rs1460922, rs4687326, and rs2686464—which included all the exons of FGF12. The results showed that the single‐nucleotide polymorphism rs1460922 in FGF12 was significantly associated with VT after adjusting for covariates of sex and age in 2 independent Chinese populations: adjusted P=0.015 (odds ratio: 1.54 [95% CI, 1.09–2.19]) in the discovery sample, adjusted P=0.018 (odds ratio: 1.64 [95% CI, 1.09–2.48]) in the replication sample, and adjusted P=2.52E‐04 (odds ratio: 1.59 [95% CI, 1.24–2.03]) in the combined sample. After resequencing all amino acid coding regions and untranslated regions of FGF12, 5 rare variations were identified. The result of western blotting revealed that a de novo functional variation, p.P211Q (1.84% of 163 patients with right ventricular outflow tract VT), could downregulate FGF12 expression significantly.ConclusionsIn this study, we observed that rs1460922 of FGF12 was significantly associated with VT and identified that a de novo variation of FGF12 may be an important genetic risk factor for the pathogenesis of VT.