Skip to main content

Advertisement

SpringerLink
Log in

A Bioinformatics Approach to the Identification of Variants Associated with Type 1 and Type 2 Diabetes Mellitus that Reside in Functionally Validated miRNAs Binding Sites

  • Original Article
  • Published:
Biochemical Genetics Aims and scope Submit manuscript

Abstract

The present work is aimed at finding variants associated with Type 1 and Type 2 diabetes mellitus (DM) that reside in functionally validated miRNAs binding sites and that can have a functional role in determining diabetes and related pathologies. Using bioinformatics analyses we obtained a database of validated polymorphic miRNA binding sites which has been intersected with genes related to DM or to variants associated and/or in linkage disequilibrium (LD) with it and is reported in genome-wide association studies (GWAS). The workflow we followed allowed us to find variants associated with DM that also reside in functional miRNA binding sites. These data have been demonstrated to have a functional role by impairing the functions of genes implicated in biological processes linked to DM. In conclusion, our work emphasized the importance of SNPs located in miRNA binding sites. The results discussed in this work may constitute the basis of further works aimed at finding functional candidates and variants affecting protein structure and function, transcription factor binding sites, and non-coding epigenetic variants, contributing to widen the knowledge about the pathogenesis of this important disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355

    Article  CAS  PubMed  Google Scholar 

  • Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  CAS  PubMed  Google Scholar 

  • Baxter AG, Jordan MA (2011) From markers to molecular mechanisms: type 1 diabetes in the post-GWAS era. Rev Diabet Stud 9:201–223

    Article  Google Scholar 

  • Bhattacharya A, Ziebarth JD, Cui Y (2014) PolymiRTS Database 3.0: linking polymorphisms in microRNAs and their target sites with human diseases and biological pathways. Nucleic Acids Res 42:D86–D91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bulik-Sullivan B, Selitsky S, Sethupathy P (2013) Prioritization of genetic variants in the microRNA regulome as functional candidates in genome-wide association studies. Hum Mutat 34:1049–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bushati N, Cohen SM (2007) MicroRNA functions. Annu Rev Cell Dev Biol 23:175–205

    Article  CAS  PubMed  Google Scholar 

  • Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866

    Article  CAS  PubMed  Google Scholar 

  • Chen K, Song F, Calin GA, Wei Q, Hao X, Zhang W (2008) Polymorphisms in microRNA targets: a gold mine for molecular epidemiology. Carcinogenesis 29:1306–1311

    Article  CAS  PubMed  Google Scholar 

  • Ciccacci C et al (2013) MicroRNA genetic variations: association with type 2 diabetes. Acta Diabetol 50:867–872

    Article  CAS  PubMed  Google Scholar 

  • Consortium GP (2012) An integrated map of genetic variation from 1092 human genomes. Nature 491:56–65

    Article  Google Scholar 

  • Cui Y (2014) In silico mapping of polymorphic miRNA-mRNA interactions in autoimmune thyroid diseases. Autoimmunity 47(5):327–333

    Article  CAS  PubMed  Google Scholar 

  • Edwards SL, Beesley J, French JD, Dunning AM (2013) Beyond GWASs: illuminating the dark road from association to function. Am J Hum Genet 93:779–797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ficarra E (2012) One decade of development and evolution of microRNA target prediction algorithms. Genom Proteom Bioinform 10:254–263

    Article  Google Scholar 

  • Guay C, Regazzi R (2013) Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat Rev Endocrinol 9:513–521

    Article  CAS  PubMed  Google Scholar 

  • Guay C, Roggli E, Nesca V, Jacovetti C, Regazzi R (2011) Diabetes mellitus, a microRNA-related disease? Transl Res 157:253–264

    Article  CAS  PubMed  Google Scholar 

  • Hafner M et al (2010) Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141:129–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Helwak A, Kudla G, Dudnakova T, Tollervey D (2013) Mapping the human miRNA interactome by CLASH reveals frequent noncanonical binding. Cell 153:654–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herrera B et al (2010) Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes. Diabetologia 53:1099–1109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci 106:9362–9367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanehisa M, Goto S (2000) KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28:27–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kloosterman WP, Plasterk RH (2006) The diverse functions of microRNAs in animal development and disease. Dev Cell 11:441–450

    Article  CAS  PubMed  Google Scholar 

  • Li J, Zhang Z (2013) miRNA regulatory variation in human evolution. Trends Genet 29:116–124

    Article  PubMed  Google Scholar 

  • Li R, Zhang P, Barker LE, Chowdhury FM, Zhang X (2010) Cost-effectiveness of interventions to prevent and control diabetes mellitus: a systematic review. Diabetes care 33:1872–1894

    Article  PubMed  PubMed Central  Google Scholar 

  • Lovis P et al (2008) Alterations in microRNA expression contribute to fatty acid–induced pancreatic β-cell dysfunction. Diabetes 57:2728–2736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu J, Clark AG (2012) Impact of microRNA regulation on variation in human gene expression. Genome Res 22:1243–1254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madhyastha R, Madhyastha H, Nakajima Y, Omura S, Maruyama M (2012) MicroRNA signature in diabetic wound healing: promotive role of miR-21 in fibroblast migration. Int Wound J 9:355–361

    Article  CAS  PubMed  Google Scholar 

  • Meola N, Gennarino VA, Banfi S (2009) microRNAs and genetic diseases. Pathogenetics 2:7

    Article  PubMed  PubMed Central  Google Scholar 

  • Nesca V et al (2013) Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes. Diabetologia 56:2203–2212

    Article  CAS  PubMed  Google Scholar 

  • Nielsen LB et al (2012) Circulating levels of microRNA from children with newly diagnosed type 1 diabetes and healthy controls: evidence that miR-25 associates to residual beta-cell function and glycaemic control during disease progression. Exp Diabetes Res 2012:896362

    PubMed  PubMed Central  Google Scholar 

  • Osipova J et al (2014) Diabetes-associated microRNAs in pediatric patients with type 1 diabetes mellitus: a cross-sectional cohort study. J Clin Endocrinol Metab 99:E1661–E1665

    Article  CAS  PubMed  Google Scholar 

  • Pasquinelli AE (2012) MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet 13:271–282

    CAS  PubMed  Google Scholar 

  • Poy MN et al (2004) A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432:226–230

    Article  CAS  PubMed  Google Scholar 

  • Poy MN et al (2009) miR-375 maintains normal pancreatic α-and β-cell mass. Proc Natl Acad Sci 106:5813–5818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prentki M, Nolan CJ (2006) Islet β cell failure in type 2 diabetes. J Clin Investig 116:1802–1812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roggli E, Gattesco S, Caille D, Briet C, Boitard C, Meda P, Regazzi R (2012) Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice. Diabetes 61:1742–1751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ryan BM, Robles AI, Harris CC (2010) Genetic variation in microRNA networks: the implications for cancer research. Nat Rev Cancer 10:389–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salas-Pérez F, Codner E, Valencia E, Pizarro C, Carrasco E, Pérez-Bravo F (2013) MicroRNAs miR-21a and miR-93 are down regulated in peripheral blood mononuclear cells (PBMCs) from patients with type 1 diabetes. Immunobiology 218:733–737

    Article  PubMed  Google Scholar 

  • Sayed D, Abdellatif M (2011) MicroRNAs in development and disease. Physiol Rev 91:827–887

    Article  CAS  PubMed  Google Scholar 

  • Sebastiani G, Grieco FA, Spagnuolo I, Galleri L, Cataldo D, Dotta F (2011) Increased expression of microRNA miR-326 in type 1 diabetic patients with ongoing islet autoimmunity. Diabetes/Metab Res Rev 27:862–866

    Article  CAS  Google Scholar 

  • Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R (2001) Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J 15:2099–2111

    Article  CAS  PubMed  Google Scholar 

  • Shantikumar S, Caporali A, Emanueli C (2012) Role of microRNAs in diabetes and its cardiovascular complications. Cardiovasc Res 93:583–593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taylor J, Schenck I, Blankenberg D, Nekrutenko A (2007) Using galaxy to perform large-scale interactive data analyses. Curr Protoc Bioinform. 10:10.5. doi:10.1002/0471250953.bi1005s19

    Google Scholar 

  • Trajkovski M et al (2011) MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474:649–653

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Liu J, Liu C, Naji A, Stoffers DA (2013) MicroRNA-7 regulates the mTOR pathway and proliferation in adult pancreatic β-cells. Diabetes 62:887–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ward LD, Kellis M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40:D930–D934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Welter D et al (2014) The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 42:D1001–D1006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Whiting DR, Guariguata L, Weil C, Shaw J (2011) IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 94:311–321

    Article  PubMed  Google Scholar 

  • Yang J-H, Li J-H, Shao P, Zhou H, Chen Y-Q, Qu L-H (2011) starBase: a database for exploring microRNA–mRNA interaction maps from Argonaute CLIP-Seq and Degradome-Seq data. Nucleic Acids Res 39:D202–D209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zampetaki A et al (2010) Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res 107:810–817

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Shahid Beheshti University of Medical Sciences for providing the fund of this work (Fund Number: 1393-1-91-13285). Also this work was supported partly by Italian Ministry of Health by providing financial support to Andrea Masotti (Ricerca Corrente 2014 and 2015).

Author information

Authors and Affiliations

  1. Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Velenjak Street, Tehran, Iran

    Hamid Ghaedi, Milad Bastami, Reza Mirfakhraie, Abolfazl Movafagh & Mir Davood Omrani

  2. Faculty of Veterinary, Shahrekord Islamic Azad University, Shahrekord, Iran

    Mohammad Mehdi Jahani

  3. Clinical Biochemistry Department, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Behnam Alipoor

  4. Medical Biotechnology Department, Pasteur Institute of Iran, Tehran, Iran

    Maryam Tabasinezhad

  5. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Omar Ghaderi

  6. Medical Genetics Department, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Ziba Nariman-Saleh-Fam

  7. Gene Expression - Microarrays Laboratory, Bambino Gesù Children’s Hospital, IRCCS, Polo di Ricerca - V.le di San Paolo 15, 00146, Rome, Italy

    Andrea Masotti

Authors
  1. Hamid Ghaedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Milad Bastami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammad Mehdi Jahani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Behnam Alipoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maryam Tabasinezhad
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Omar Ghaderi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ziba Nariman-Saleh-Fam
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Reza Mirfakhraie
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Abolfazl Movafagh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mir Davood Omrani
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Andrea Masotti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mir Davood Omrani or Andrea Masotti.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 56 kb)

Supplementary material 2 (DOCX 26 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ghaedi, H., Bastami, M., Jahani, M.M. et al. A Bioinformatics Approach to the Identification of Variants Associated with Type 1 and Type 2 Diabetes Mellitus that Reside in Functionally Validated miRNAs Binding Sites. Biochem Genet 54, 211–221 (2016). https://doi.org/10.1007/s10528-016-9713-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10528-016-9713-5

Keywords

Search

Navigation