Association Study of ANRIL Genetic Variants and Multiple Sclerosis

Rezazadeh, Maryam; Gharesouran, Jalal; Moradi, Mohsen; Noroozi, Rezvan; Omrani, Mir Davood; Ghafouri‐Fard, Soudeh

doi:10.1007/s12031-018-1069-3

Cited by 31 publications

(25 citation statements)

References 28 publications

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“…With respect to the role of lnc‐ANRIL in immunity, another critical regulator in sepsis, there have been a few studies illuminating that lnc‐ANRIL might involve in immune disorder related diseases. A study elucidates that the genetic variations of lnc‐ANRIL, which are CCGG and TAAA haplotypes, have a protective effect against multiple sclerosis (MS) in MS patients . However, the mechanistic process of lnc‐ANRIL in regulating immune disorder is still not evaluated, more experimental studies are needed in the future.…”

Section: Discussionmentioning

confidence: 99%

“…With respect to the values of noncoding RNAs to be biomarkers or therapeutic targets in sepsis patients, long noncoding RNA (lncRNA) and microRNA (miRNA) are the most implicated ones . Lnc‐antisense noncoding RNA in the INK4 locus (ANRIL) is a lncRNA located on chromosome 9p21 region and transcribed by RNA polymerase II and is indicated in the regulation of inflammation and immune responses . miR‐125a, a highly reserved miRNA locating on chromosome 19, 11, and 21, is also closely related to inflammation and immunity, and this miRNA has been reported to have the potential in regulating sepsis pathogenesis .…”

Section: Introductionmentioning

confidence: 99%

“…11,12 Lnc-antisense noncoding RNA in the INK4 locus (ANRIL) is a lncRNA located on chromosome 9p21 region and transcribed by RNA polymerase II and is indicated in the regulation of inflammation and immune responses. 13,14 miR-125a, a highly reserved miRNA locating on chromosome 19, 11, and 21, is also closely related to inflammation and immunity, and this miRNA has been reported to have the potential in regulating sepsis pathogenesis. 15,16 Moreover, it is a direct target of lnc-ANRIL, and the lnc-ANRIL/miR-125a axis has been indicated in many diseases.…”

Section: Introductionmentioning

confidence: 99%

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Elevated circulating lnc‐ANRIL/miR‐125a axis level predicts higher risk, more severe disease condition, and worse prognosis of sepsis

Gui

Peng

Liu

2019

Clinical Laboratory Analysis

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Aim This study aimed to investigate the correlation of lnc‐ANRIL/miR‐125a axis with risk, severity, inflammation, and prognosis of sepsis. Methods A hundred and twenty‐six sepsis patients and 125 healthy controls were recruited, and then, blood samples were collected, and plasma was separated for lnc‐ANRIL, miR‐125a, lnc‐ANRIL/miR‐125a axis, and inflammatory cytokine level detections. In addition, basic characteristics, 28‐day mortality, and accumulating survival of sepsis patients were recorded. Results Plasma lnc‐ANRIL expression was increased, miR‐125a expression was decreased, and lnc‐ANRIL/miR‐125a axis level was elevated in sepsis patients compared with healthy controls, and all of them had good value for predicting sepsis risk with AUCs of 0.800, 0.817, and 0.843, respectively. Lnc‐ANRIL and lnc‐ANRIL/miR‐125a axis were positively correlated with biochemical index levels including CRP and PCT levels, disease severity scale scores, and pro‐inflammatory cytokine levels in sepsis patients, while miR‐125a displayed the opposite trend. Lnc‐ANRIL and lnc‐ANRIL/miR‐125a axis expressions were elevated, while miR‐125a expression was declined in deaths compared with survivors, and all of them predicted 28‐day mortality in sepsis patients with AUCs of 0.765, 0.745, and 0.785, respectively. Subsequently, the Kaplan‐Meier analysis revealed that patients with high lnc‐ANRIL, low miR‐125a, and high lnc‐ANRIL/miR‐125a axis levels presented with worse accumulating survival. In addition, multivariate regression model analyses revealed that high plasma lnc‐ANRIL/miR‐125a axis was an independent predictive factor for both increased 28‐day mortality and worse accumulating survival. Conclusion Circulating lnc‐ANRIL/miR‐125a axis was upregulated and could serve as a biomarker for severity, inflammation, and prognosis in sepsis patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Elevated circulating lnc‐ANRIL/miR‐125a axis level predicts higher risk, more severe disease condition, and worse prognosis of sepsis

Gui

Peng

Liu

2019

Clinical Laboratory Analysis

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“…Studies indicate that SNPs in the ANRIL gene can impact ANRIL expression and function. The CDKN2A/B locus is associated with risk of cancer, atherosclerotic disease, type 2 diabetes, stroke, aneurysm, periodontitis, Alzheimer's disease, aging, frailty, glaucoma, endometriosis, multiple sclerosis, hypertension ( 10 , 61 ). Reviewed here are only SNPs within or downstream of the ANRIL gene; broader CDKN2A/B locus disease associations have been reviewed previously ( 10 , 62 ).…”

Section: The Anril Gene Is Associated With Human Dmentioning

confidence: 99%

ANRIL: A lncRNA at the CDKN2A/B Locus With Roles in Cancer and Metabolic Disease

2018

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The CDKN2A/B genomic locus is associated with risk of human cancers and metabolic disease. Although the locus contains several important protein-coding genes, studies suggest disease roles for a lesser-known antisense lncRNA encoded at this locus, called ANRIL. ANRIL is a complex gene containing at least 21 exons in simians, with many reported linear and circular isoforms. Like other genes, abundance of ANRIL is regulated by epigenetics, classic transcription regulation, splicing, and post-transcriptional influences such as RNA stability and microRNAs. Known molecular functions of ANRIL include in cis and in trans gene regulation through chromatin modification complexes, and influence over microRNA signaling networks. Polymorphisms at the ANRIL gene are linked to risk for many different cancers, as well as risk of atherosclerotic cardiovascular disease, bone mass, obesity and type 2 diabetes. A broad array of variable reported impacts of polymorphisms on ANRIL abundance, splicing and function suggests that ANRIL has cell-type and context-dependent regulation and actions. In cancer cells, ANRIL gain of function increases proliferation, metastasis, cell survival and epithelial-mesenchymal transformation, whereas ANRIL loss of function decreases tumor size and growth, invasion and metastasis, and increases apoptosis and senescence. In metabolic disease, polymorphisms at the ANRIL gene are linked to risk of type 2 diabetes, coronary artery disease, coronary artery calcium score, myocardial infarction, and stroke. Intriguingly, with the exception of one polymorphism in exon 2 of ANRIL, the single nucleotide polymorphisms (SNPs) associated with atherosclerosis and diabetes are non-overlapping. Evidence suggests that ANRIL gain of function increases atherosclerosis; in diabetes, a risk-SNP reduced the pancreatic beta cell proliferation index. Studies are limited by the uncertain relevance of rodent models to ANRIL studies, since most ANRIL exons do not exist in mouse. Diverse cell-type-dependent results suggest it is necessary to perform studies in the relevant primary human tissue for each disease. Much remains to be learned about the biology of ANRIL in human health and disease; this research area may lead to insight into disease mechanisms and therapeutic approaches.

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“…These results suggest lncRNA transcripts may play a mechanistic role in the differentiation of T cell lineages thought to be associated with CNS autoimmunity and demyelination. Other studies have selected candidates based on previously described associations with immune disorders and used RT-qPCR to compare MS participants to controls (Dastmalchi et al, 2018;Eftekharian et al, 2017;Ganji et al, 2019;Gharesouran et al, 2018;Gharesouran et al, 2019;Gharzi et al, 2018;Santoro et al, 2016), or analysis of polymorphic variation (Mahdi Eftekharian et al, 2019;Rezazadeh et al, 2018). This latter type of study raises the possibility that noncoding sequence variants may have an important effect on lncRNA function and MS pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Long noncoding RNAs associated with phenotypic severity in multiple sclerosis

Gupta

Martens

Metz

et al. 2019

Multiple Sclerosis and Related Disorders

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Introduction: Multiple sclerosis (MS) is a disease that causes progressive neurological disability. Treatments are available that are protective against MS relapses and it is thought that reduction of early neuroinflammation may improve long term prognosis. At present there is no biomarker that can predict which patients may have a more severe disease course, and potentially benefit from more aggressive therapy. Long noncoding RNAs (lncRNAs) are emerging as potential disease biomarkers that could be of interest in prognostication of MS. Methods: We identified a discovery cohort of 20 patients, ten of which had a mild MS phenotype and ten with severe MS phenotype according to the Age-Related MS Severity Scale (ARMSS). RNAseq was performed on RNA extracted from whole blood and bioinformatic analysis restricted to lncRNAs. Our goal was to select the most significant lncRNAs and quantify these using custom digital droplet RT-qPCR assays in a validation cohort of 44 participants (with mild or severe MS). Results: Eight lncRNA candidates were identified from the discovery cohort. Of these, four lncRNAs remained significantly differentially expressed in the validation cohort (ENSG00000260302, ENSG00000270972, ENSG00000272512 and ENSG00000223387). Little is known about the precise roles of these lncRNAs but based on expression data they appear to be important to immune function and are of potential biological significance to MS pathogenesis. Conclusions: This study is the first to investigate possible lncRNA biomarkers to differentiate phenotypic severity in MS. Although the findings are preliminary based on our small sample size, they are sufficient to identify hypotheses for future investigation, and give guidance regarding the design of future studies.

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Association Study of ANRIL Genetic Variants and Multiple Sclerosis

Cited by 31 publications

References 28 publications

Elevated circulating lnc‐ANRIL/miR‐125a axis level predicts higher risk, more severe disease condition, and worse prognosis of sepsis

Elevated circulating lnc‐ANRIL/miR‐125a axis level predicts higher risk, more severe disease condition, and worse prognosis of sepsis

ANRIL: A lncRNA at the CDKN2A/B Locus With Roles in Cancer and Metabolic Disease

Long noncoding RNAs associated with phenotypic severity in multiple sclerosis

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