Biochemical Genetics

, Volume 54, Issue 3, pp 211–221 | Cite as

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

  • Hamid Ghaedi
  • Milad Bastami
  • Mohammad Mehdi Jahani
  • Behnam Alipoor
  • Maryam Tabasinezhad
  • Omar Ghaderi
  • Ziba Nariman-Saleh-Fam
  • Reza Mirfakhraie
  • Abolfazl Movafagh
  • Mir Davood OmraniEmail author
  • Andrea MasottiEmail author
Original Article


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.


Diabetes mellitus Genome-wide association study MicroRNA Single nucleotide polymorphism Target site 



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).

Supplementary material

10528_2016_9713_MOESM1_ESM.docx (56 kb)
Supplementary material 1 (DOCX 56 kb)
10528_2016_9713_MOESM2_ESM.docx (27 kb)
Supplementary material 2 (DOCX 26 kb)


  1. Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355CrossRefPubMedGoogle Scholar
  2. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297CrossRefPubMedGoogle Scholar
  3. Baxter AG, Jordan MA (2011) From markers to molecular mechanisms: type 1 diabetes in the post-GWAS era. Rev Diabet Stud 9:201–223CrossRefGoogle Scholar
  4. 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–D91CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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 34:1049–1056CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bushati N, Cohen SM (2007) MicroRNA functions. Annu Rev Cell Dev Biol 23:175–205CrossRefPubMedGoogle Scholar
  7. Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866CrossRefPubMedGoogle Scholar
  8. Chen K, Song F, Calin GA, Wei Q, Hao X, Zhang W (2008) Polymorphisms in microRNA targets: a gold mine for molecular epidemiology. Carcinogenesis 29:1306–1311CrossRefPubMedGoogle Scholar
  9. Ciccacci C et al (2013) MicroRNA genetic variations: association with type 2 diabetes. Acta Diabetol 50:867–872CrossRefPubMedGoogle Scholar
  10. Consortium GP (2012) An integrated map of genetic variation from 1092 human genomes. Nature 491:56–65CrossRefGoogle Scholar
  11. Cui Y (2014) In silico mapping of polymorphic miRNA-mRNA interactions in autoimmune thyroid diseases. Autoimmunity 47(5):327–333CrossRefPubMedGoogle Scholar
  12. Edwards SL, Beesley J, French JD, Dunning AM (2013) Beyond GWASs: illuminating the dark road from association to function. Am J Hum Genet 93:779–797CrossRefPubMedPubMedCentralGoogle Scholar
  13. Ficarra E (2012) One decade of development and evolution of microRNA target prediction algorithms. Genom Proteom Bioinform 10:254–263CrossRefGoogle Scholar
  14. Guay C, Regazzi R (2013) Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat Rev Endocrinol 9:513–521CrossRefPubMedGoogle Scholar
  15. Guay C, Roggli E, Nesca V, Jacovetti C, Regazzi R (2011) Diabetes mellitus, a microRNA-related disease? Transl Res 157:253–264CrossRefPubMedGoogle Scholar
  16. Hafner M et al (2010) Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141:129–141CrossRefPubMedPubMedCentralGoogle Scholar
  17. Helwak A, Kudla G, Dudnakova T, Tollervey D (2013) Mapping the human miRNA interactome by CLASH reveals frequent noncanonical binding. Cell 153:654–665CrossRefPubMedPubMedCentralGoogle Scholar
  18. Herrera B et al (2010) Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes. Diabetologia 53:1099–1109CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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 106:9362–9367CrossRefPubMedPubMedCentralGoogle Scholar
  20. Kanehisa M, Goto S (2000) KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28:27–30CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kloosterman WP, Plasterk RH (2006) The diverse functions of microRNAs in animal development and disease. Dev Cell 11:441–450CrossRefPubMedGoogle Scholar
  22. Li J, Zhang Z (2013) miRNA regulatory variation in human evolution. Trends Genet 29:116–124CrossRefPubMedGoogle Scholar
  23. 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 33:1872–1894CrossRefPubMedPubMedCentralGoogle Scholar
  24. Lovis P et al (2008) Alterations in microRNA expression contribute to fatty acid–induced pancreatic β-cell dysfunction. Diabetes 57:2728–2736CrossRefPubMedPubMedCentralGoogle Scholar
  25. Lu J, Clark AG (2012) Impact of microRNA regulation on variation in human gene expression. Genome Res 22:1243–1254CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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 9:355–361CrossRefPubMedGoogle Scholar
  27. Meola N, Gennarino VA, Banfi S (2009) microRNAs and genetic diseases. Pathogenetics 2:7CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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 56:2203–2212CrossRefPubMedGoogle Scholar
  29. 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 2012:896362PubMedPubMedCentralGoogle Scholar
  30. 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–E1665CrossRefPubMedGoogle Scholar
  31. Pasquinelli AE (2012) MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet 13:271–282PubMedGoogle Scholar
  32. Poy MN et al (2004) A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432:226–230CrossRefPubMedGoogle Scholar
  33. Poy MN et al (2009) miR-375 maintains normal pancreatic α-and β-cell mass. Proc Natl Acad Sci 106:5813–5818CrossRefPubMedPubMedCentralGoogle Scholar
  34. Prentki M, Nolan CJ (2006) Islet β cell failure in type 2 diabetes. J Clin Investig 116:1802–1812CrossRefPubMedPubMedCentralGoogle Scholar
  35. 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 61:1742–1751CrossRefPubMedPubMedCentralGoogle Scholar
  36. Ryan BM, Robles AI, Harris CC (2010) Genetic variation in microRNA networks: the implications for cancer research. Nat Rev Cancer 10:389–402CrossRefPubMedPubMedCentralGoogle Scholar
  37. 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 218:733–737CrossRefPubMedGoogle Scholar
  38. Sayed D, Abdellatif M (2011) MicroRNAs in development and disease. Physiol Rev 91:827–887CrossRefPubMedGoogle Scholar
  39. 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 27:862–866CrossRefGoogle Scholar
  40. 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 15:2099–2111CrossRefPubMedGoogle Scholar
  41. Shantikumar S, Caporali A, Emanueli C (2012) Role of microRNAs in diabetes and its cardiovascular complications. Cardiovasc Res 93:583–593CrossRefPubMedPubMedCentralGoogle Scholar
  42. 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
  43. Trajkovski M et al (2011) MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474:649–653CrossRefPubMedGoogle Scholar
  44. 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 62:887–895CrossRefPubMedPubMedCentralGoogle Scholar
  45. 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–D934CrossRefPubMedPubMedCentralGoogle Scholar
  46. Welter D et al (2014) The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 42:D1001–D1006CrossRefPubMedPubMedCentralGoogle Scholar
  47. 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 94:311–321CrossRefPubMedGoogle Scholar
  48. 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–D209CrossRefPubMedPubMedCentralGoogle Scholar
  49. Zampetaki A et al (2010) Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res 107:810–817CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Hamid Ghaedi
    • 1
  • Milad Bastami
    • 1
  • Mohammad Mehdi Jahani
    • 2
  • Behnam Alipoor
    • 3
  • Maryam Tabasinezhad
    • 4
  • Omar Ghaderi
    • 5
  • Ziba Nariman-Saleh-Fam
    • 6
  • Reza Mirfakhraie
    • 1
  • Abolfazl Movafagh
    • 1
  • Mir Davood Omrani
    • 1
    Email author
  • Andrea Masotti
    • 7
    Email author
  1. 1.Medical Genetics Department, Faculty of MedicineShahid Beheshti University of Medical SciencesTehranIran
  2. 2.Faculty of VeterinaryShahrekord Islamic Azad UniversityShahrekordIran
  3. 3.Clinical Biochemistry Department, Faculty of MedicineTehran University of Medical SciencesTehranIran
  4. 4.Medical Biotechnology DepartmentPasteur Institute of IranTehranIran
  5. 5.Department of Pharmaceutical Biotechnology, Faculty of PharmacyTehran University of Medical SciencesTehranIran
  6. 6.Medical Genetics Department, Faculty of MedicineTehran University of Medical SciencesTehranIran
  7. 7.Gene Expression - Microarrays LaboratoryBambino Gesù Children’s Hospital, IRCCSRomeItaly

Personalised recommendations