Association study of the miRNA-binding site polymorphisms of CDKN2A/B genes with gestational diabetes mellitus susceptibility

Wang, Xiaojing; Li, Wei; Ma, Liangkun; Gao, Jinsong; Liu, Juntao; Ping, Fan; Nie, Min

doi:10.1007/s00592-015-0768-2

Cited by 26 publications

(19 citation statements)

References 34 publications

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“…P53 was reported to regulate gene expression through its interaction with transcriptional factors and is downregulated in diabetes (13). Activation of β cell glucokinase, initially triggers replication, then results in apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor P53 (24).…”

Section: Resultsmentioning

confidence: 99%

“…Through suppressing key genes involved in disease development and progression, miRNAs can affect many disease-related signaling pathways via local or systemic regulation (12). The association between changes in miRNA expression and the development of diabetes neuropathy presents us with a new angle to explore pathogenesis and progression of diabetes: In diabetes, several miRNAs including miR-590-3p, miR-155 and miR-323b-5p have been demonstrated to be associated with genesis and prognosis of diabetes patients (13–15). Limited studies have been performed on miRNA expression profiles in patients with DN, especially in DN-induced pain, and miRNA expression has not previously been linked to SerpinE2 (16).…”

Section: Introductionmentioning

confidence: 99%

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miR-199a-3p is involved in the pathogenesis and progression of diabetic neuropathy through downregulation of SerpinE2

Liu

et al. 2017

Molecular Medicine Reports

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The present study aimed to investigate the expression status of miRNA-199a-3p in patients with diabetic neuropathy (DN) and the mechanism by which this miRNA is involved in the genesis of DN. The expression of miRNA-199a-3p in plasma of peripheral blood was compared between patients with diabetes and a family history of diabetes and control volunteers by reverse transcription-quantitative polymerase chain reaction (RT-qPCR); in 60 diabetes patients, 45 (75%) demosntrated upregulated miR-199a-3p expression compared with control volunteer plasma. RT-qPCR was also used to detect miRNA-199a-3p expression in paired lower limb skin tissues from 30 patients with DN and 20 control volunteers; miR-199a-3p expression in patients with DN was significantly higher than in the control group. Next miR-199a-3p expression levels were evaluated with respect to the clinic-pathological parameters of diabetes; increased expression of miR-199a-3p was significantly associated with increased disease duration (P=0.041), glycated hemoglobin (HbA1C) levels (P=0.033), and fibrinogen levels (P=0.003). Finally, the effects on downstream mRNA expression levels were investigated as a result of manipulating miR-199a-3p levels. miR-199a-3p overexpression inhibited the expression of the extracellular serine protease inhibitor E2 (SerpinE2). Therefore, it may be hypothesized that miR-199a-3p can induce DN via promoting coagulation in skin peripheral circulation, through the downregulation of SerpinE2. The present findings suggested that miR-199a-3p may have potential as a novel therapeutic target for the treatment of patients with DN.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

miR-199a-3p is involved in the pathogenesis and progression of diabetic neuropathy through downregulation of SerpinE2

Liu

et al. 2017

Molecular Medicine Reports

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“…Disease-associated SNPs are predicted to disrupt transcription factor binding sites, including some factors with known roles in beta cell development or survival, including, v-maf avian musculoaponeurotic fibrosarcoma oncogene homologue B (MAFB), NK homeobox protein 6.1 (NKX6.1), nuclear factor of activated T lymphocytes (NFAT), FOXA2, forkhead box A2 (FOXA2), nuclear factor κβ (NFκB), hepatocyte nuclear factor 1 (HNF1) and CCAAT-enhancer-binding protein homologous protein (CHOP) [90, 192, 194]. Polymorphisms may also impact microRNA regulation of transcription or translation [195], although most SNPs at the type 2 diabetes locus are non-coding. An enhancer identified in tumours, RD INK4/ARF , interacts with oncoproteins to silence the CDKN2A/B locus [196, 197].…”

Section: How Might Cdkn2a/b Polymorphisms Influence Type 2 Diabetes Rmentioning

confidence: 99%

Islet biology, the CDKN2A/B locus and type 2 diabetes risk

et al. 2016

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Type 2 diabetes, fuelled by the obesity epidemic, is an escalating worldwide cause of personal hardship and public cost. Diabetes incidence increases with age, and many studies link the classic senescence and ageing protein p16INK4A to diabetes pathophysiology via pancreatic islet biology. Genome-wide association studies (GWASs) have unequivocally linked the CDKN2A/B locus, which encodes p16 inhibitor of cyclin-dependent kinase (p16INK4A) and three other gene products, p14 alternate reading frame (p14ARF), p15INK4B and antisense non-coding RNA in the INK4 locus (ANRIL), with human diabetes risk. However, the mechanism by which the CDKN2A/B locus influences diabetes risk remains uncertain. Here, we weigh the evidence that CDKN2A/B polymorphisms impact metabolic health via islet biology vs effects in other tissues. Structured in a bedside-to-bench-to-bedside approach, we begin with a summary of the evidence that the CDKN2A/B locus impacts diabetes risk and a brief review of the basic biology of CDKN2A/B gene products. The main emphasis of this work is an in-depth look at the nuanced roles that CDKN2A/B gene products and related proteins play in the regulation of beta cell mass, proliferation and insulin secretory function, as well as roles in other metabolic tissues. We finish with a synthesis of basic biology and clinical observations, incorporating human physiology data. We conclude that it is likely that the CDKN2A/B locus influences diabetes risk through both islet and non-islet mechanisms.

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“…Increasing evidence suggests that dysregulated miRNAs directly contribute to the pathogenesis of a variety of human diseases [30][31][32][33][34]. SNPs in miRNA target sites in the 3' UTR of mRNAs are referred to as polymorphisms in microRNAs and their target sites (polymiRTSs) and can affect mRNA half-life, resulting in decreased protein levels due to mRNAmiRNA interactions and increased susceptibility to many diseases [30-33, 35, 36], including PD [33].…”

Section: Discussionmentioning

confidence: 99%

miR-486-3p Influences the Neurotoxicity of a-Synuclein by Targeting the SIRT2 Gene and the Polymorphisms at Target Sites Contributing to Parkinson’s Disease

Wang

Cai

Huang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Increasing evidence suggests the important role of sirtuin 2 (SIRT2) in the pathology of Parkinson’s disease (PD). However, the association between potential functional polymorphisms in the SIRT2 gene and PD still needs to be identified. Exploring the molecular mechanism underlying this potential association could also provide novel insights into the pathogenesis of this disorder. Methods: Bioinformatics analysis and screening were first performed to find potential microRNAs (miRNAs) that could target the SIRT2 gene, and molecular biology experiments were carried out to further identify the regulation between miRNA and SIRT2 and characterize the pivotal role of miRNA in PD models. Moreover, a clinical case-control study was performed with 304 PD patients and 312 healthy controls from the Chinese Han population to identify the possible association of single nucleotide polymorphisms (SNPs) within the miRNA binding sites of SIRT2 with the risk of PD. Results: Here, we demonstrate that miR-486-3p binds to the 3’ UTR of SIRT2 and influences the translation of SIRT2. MiR-486-3p mimics can decrease the level of SIRT2 and reduce a-synuclein (α-syn)-induced aggregation and toxicity, which may contribute to the progression of PD. Interestingly, we find that a SNP, rs2241703, may disrupt miR-486-3p binding sites in the 3’ UTR of SIRT2, subsequently influencing the translation of SIRT2. Through the clinical case-control study, we further verify that rs2241703 is associated with PD risk in the Chinese Han population. Conclusion: The present study confirms that the rs2241703 polymorphism in the SIRT2 gene is associated with PD in the Chinese Han population, provides the potential mechanism of the susceptibility locus in determining PD risk and reveals a potential target of miRNA for the treatment and prevention of PD.

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Association study of the miRNA-binding site polymorphisms of CDKN2A/B genes with gestational diabetes mellitus susceptibility

Abstract: The CC genotype of CDKN2B rs1063192 in the hsa-miR-323b-5p binding site increased the risk of GDM in pregnant Chinese Han women. Importantly, our study provides evidence that miR-binding SNPs are a novel source of GDM susceptibility loci.

Cited by 26 publications

References 34 publications

miR-199a-3p is involved in the pathogenesis and progression of diabetic neuropathy through downregulation of SerpinE2

miR-199a-3p is involved in the pathogenesis and progression of diabetic neuropathy through downregulation of SerpinE2

Islet biology, the CDKN2A/B locus and type 2 diabetes risk

miR-486-3p Influences the Neurotoxicity of a-Synuclein by Targeting the SIRT2 Gene and the Polymorphisms at Target Sites Contributing to Parkinson’s Disease

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