Skip to main content
SpringerLink
Log in

Type 2 diabetes is associated with the MTNR1B gene, a genetic bridge between circadian rhythm and glucose metabolism, in a Turkish population

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Type 2 diabetes (T2D) is a complicated public health problem in Turkey as well as worldwide. Genome-wide approaches have been guiding in very challenging situations, such as the elucidation of genetic variations underlying complex diseases such as T2D. Despite intensive studies worldwide, few studies have determined the genetic susceptibility to T2D in Turkish populations. In this study, we investigated the effect of genes that are strongly associated with T2D in genome-wide association (GWA) studies, including MTNR1B, CDKAL1, THADA, ADAMTS9 and ENPP1, on T2D and its characteristic traits in a Turkish population. In 824 nonobese individuals (454 T2D patients and 370 healthy individuals), prominent variants of these GWA genes were genotyped by real-time PCR using the LightSNiP Genotyping Assay System. The SNP rs1387153 C/T, which is located 28 kb upstream of the MTNR1B gene, was significantly associated with T2D and fasting blood glucose levels (P < 0.05). The intronic SNP rs10830963 C/G in the MTNR1B gene was not associated with T2D, but it was associated with fasting blood glucose, HbA1C and LDL levels (P < 0.05). The other important GWA loci investigated in our study were not found to be associated with T2D or its traits. Only the SNP rs1044498 (A/C variation) in the ENPP1 gene was determined to be related to fasting blood glucose (P < 0.05). Our study suggests, consistent with the literature, that the MTNR1B locus, which has a prominent role in glucose regulation, is associated with T2D development by affecting blood glucose levels in our population.

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

Similar content being viewed by others

Data availability

The authors confirm that the data supporting the findings of the study are available within the article.

References

  1. Satman I, Yilmaz T, Sengul A, Salman S, Salman F, Uygur S et al (2002) Population-based study of diabetes and risk characteristics in Turkey: results of the Turkish diabetes epidemiology study (TURDEP). Diabetes Care 25(9):1551–1556

    Article  PubMed  Google Scholar 

  2. Satman I, Omer B, Tutuncu Y, Kalaca S, Gedik S, Dinccag N et al (2013) Twelve-year trends in the prevalence and risk factors of diabetes and prediabetes in Turkish adults. Eur J Epidemiol 28(2):169–180

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gaunt TR, Rodriguez S, Zapata C, Day IN (2006) MIDAS: software for analysis and visualisation of interallelic disequilibrium between multiallelic markers. BMC Bioinform 7(1):227

    Article  Google Scholar 

  4. Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445(7130):881–885

    Article  CAS  PubMed  Google Scholar 

  5. Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP et al (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42(7):579–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T et al (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40(5):638–645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Scott RA, Scott LJ, Mägi R, Marullo L, Gaulton KJ, Kaakinen M et al (2017) An expanded genome-wide association study of type 2 diabetes in Europeans. Diabetes 66(11):2888–2902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. McCarthy MI (2017) Genetics of T2D in 2016: biological and translational insights from T2D genetics. Nat Rev Endocrinol 13(2):71–72

    Article  CAS  PubMed  Google Scholar 

  9. Prasad RB, Groop L (2015) Genetics of type 2 diabetes-pitfalls and possibilities. Genes 6(1):87–123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Unoki H, Takahashi A, Kawaguchi T, Hara K, Horikoshi M, Andersen G et al (2008) SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet 40(9):1098–1102

    Article  CAS  PubMed  Google Scholar 

  11. Chang YC, Chiu YF, Liu PH, Shih KC, Lin MW, Sheu WH et al (2012) Replication of genome-wide association signals of type 2 diabetes in Han Chinese in a prospective cohort. Clin Endocrinol 76(3):365–372

    Article  CAS  Google Scholar 

  12. Imamura M, Maeda S, Yamauchi T, Hara K, Yasuda K, Morizono T et al (2012) A single-nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations. Hum Mol Genet 21(13):3042–3049

    Article  CAS  PubMed  Google Scholar 

  13. Hara K, Fujita H, Johnson TA, Yamauchi T, Yasuda K, Horikoshi M et al (2014) Genome-wide association study identifies three novel loci for type 2 diabetes. Hum Mol Genet 23(1):239–246

    Article  CAS  PubMed  Google Scholar 

  14. Gonen MS, Arikoglu H, Erkoc Kaya D, Ozdemir H, Ipekci SH, Arslan A et al (2012) Effects of single nucleotide polymorphisms in K(ATP) channel genes on type 2 diabetes in a Turkish population. Arch Med Res 43(4):317–323

    Article  CAS  PubMed  Google Scholar 

  15. Arikoglu H, Ozdemir H, Erkoc Kaya D, Ipekci SH, Arslan A, Kayis SA et al (2014) The adiponectin variants contribute to the genetic background of type 2 diabetes in Turkish population. Gene 534(1):10–16

    Article  CAS  PubMed  Google Scholar 

  16. Arikoglu H, Aksoy Hepdoğru M, Erkoc Kaya D, Asik A, Ipekci SH, Iscioglu F (2014) IRS1 gene polymorphisms Gly972Arg and Ala513Pro are not associated with insulin resistance and type 2 diabetes risk in non-obese Turkish population. Meta Gene 2:579–585

    Article  PubMed  PubMed Central  Google Scholar 

  17. Erkoc Kaya D, Arikoglu H, Kayis SA, Ozturk O, Gonen MS (2017) Transcription factor 7-like 2 (TCF7L2) gene polymorphisms are strong predictorsof type 2 diabetes among nonobese diabetics in the Turkish population. Turk J Med Sci 47(1):22–28

    Article  CAS  PubMed  Google Scholar 

  18. Karadogan AH, Arikoglu H, Gokturk F, Iscioglu F, Ipekci SH (2018) PIK3R1 gene polymorphisms are associated with type 2 diabetes and related features in the Turkish population. Adv Clin Exp Med 27(7):921–927

    Article  PubMed  Google Scholar 

  19. Horita N, Kaneko T (2015) Genetic model selection for a case-control study and a meta analysis. Meta Gene 5:1–8

    Article  PubMed  PubMed Central  Google Scholar 

  20. Billings LK, Florez JC (2010) The genetics of type 2 diabetes: what have we learned from GWAS? Ann NY Acad Sci 1212:59–77

    Article  CAS  PubMed  Google Scholar 

  21. Bouatia-Naji N, Bonnefond A, Cavalcanti-Proenca C, Sparso T, Holmkvist J, Marchand M et al (2009) A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet 41(1):89–94

    Article  CAS  PubMed  Google Scholar 

  22. Dashti HS, Follis JL, Smith CE, Tanaka T, Garaulet M, Gottlieb DJ et al (2015) Gene-environment interactions of circadian-related genes for cardiometabolic traits. Diabetes Care 38:1456–1466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Patel R, Rathwa N, Palit SP, Ramachandran AV, Begum R (2018) Association of melatonin & MTNR1B variants with type 2 diabetes in Gujarat population. Biomed Pharmacother 103:429–434

    Article  CAS  PubMed  Google Scholar 

  24. Van Cauter E (1998) Putative roles of melatonin in glucose regulation. Therapie 53(5):467–472

    PubMed  Google Scholar 

  25. Blodgett DM, Nowosielska A, Afik S, Pechhold S, Cura AJ, Kennedy NJ et al (2015) Novel Observations from next-generation RNA sequencing of highly purified human adult and fetal islet cell subsets. Diabetes 64(9):3172–3181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G et al (2009) Variants in MTNR1B influence fasting glucose levels. Nat Genet 41(1):77–81

    Article  CAS  PubMed  Google Scholar 

  27. Bonnefond A, Froguel P (2017) The case for too little melatonin signalling in increased diabetes risk. Diabetologia 60(5):823–825

    Article  CAS  PubMed  Google Scholar 

  28. Lyssenko V, Nagorny CL, Erdos MR, Wierup N, Jonsson A, Spegel P et al (2009) Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet 41(1):82–88

    Article  CAS  PubMed  Google Scholar 

  29. Simonis-Bik AM, Nijpels G, van Haeften TW, Houwing-Duistermaat JJ, Boomsma DI, Reiling E et al (2010) Gene variants in the novel type 2 diabetes loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B affect different aspects of pancreatic beta-cell function. Diabetes 59(1):293–301

    Article  CAS  PubMed  Google Scholar 

  30. Marouli E, Kanoni S, Mamakou V, Hackinger S, Southam L, Prins B et al (2017) Evaluating the glucose raising effect of established loci via a genetic risk score. PLoS ONE 12(11):e0186669

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ronn T, Wen J, Yang Z, Lu B, Du Y, Groop L et al (2009) A common variant in MTNR1B, encoding melatonin receptor 1B, is associated with type 2 diabetes and fasting plasma glucose in Han Chinese individuals. Diabetologia 52(5):830–833

    Article  CAS  PubMed  Google Scholar 

  32. Palmer ND, Goodarzi MO, Langefeld CD, Wang N, Guo X, Taylor KD et al (2015) Genetic variants associated with quantitative glucose homeostasis traits translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (genetics underlying diabetes in hispanics) consortium. Diabetes 64(5):1853–1866

    Article  CAS  PubMed  Google Scholar 

  33. Oh S-W, Lee J-E, Shin E, Kwon H, Choe EK, Choi S-Y et al (2020) Genome-wide association study of metabolic syndrome in Korean populations. PLoS ONE 15(1):e0227357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gaulton KJ, Ferreira T, Lee Y, Raimondo A, Magi R, Reschen ME et al (2015) Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nat Genet 47(12):1415–1425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Furey TS (2012) ChIP-seq and beyond: new and improved methodologies to detect and characterize protein-DNA interactions. Nat Rev Genet 13(12):840–852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mathelier A, Shi W, Wasserman WW (2015) Identification of altered cis-regulatory elements in human disease. Trends Genet 31(2):67–76

    Article  CAS  PubMed  Google Scholar 

  37. Tuomi T, Nagorny CLF, Singh P, Bennet H, Yu Q, Alenkvist I et al (2016) Increased melatonin signaling is a risk factor for type 2 diabetes. Cell Metab 23(6):1067–1077

    Article  CAS  PubMed  Google Scholar 

  38. Peschke E, Bach AG, Muhlbauer E (2006) Parallel signaling pathways of melatonin in the pancreatic beta-cell. J Pineal Res 40(2):184–191

    Article  CAS  PubMed  Google Scholar 

  39. Bonnefond A, Froguel P (2017) Disentangling the role of melatonin and its receptor MTNR1B in type 2 diabetes: still a long way to go? Curr Diabetes Rep 17(12):122

    Article  Google Scholar 

  40. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H et al (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316(5829):1336–1341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lee YH, Kang ES, Kim SH, Han SJ, Kim CH, Kim HJ et al (2008) Association between polymorphisms in SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1, KCNQ1 and type 2 diabetes in the Korean population. J Hum Genet 53(11–12):991–998

    Article  CAS  PubMed  Google Scholar 

  42. Cauchi S, Meyre D, Durand E, Proenca C, Marre M, Hadjadi S et al (2008) Post genome-wide association studies of novel genes associated with type 2 diabetes show gene-gene interaction and high predictive value. PLoS ONE 3:e2031

    Article  PubMed  PubMed Central  Google Scholar 

  43. Liu X, Liang J, Geng H, Xu W, Teng F, Yang M (2020) Association of the CDKAL1 polymorphism rs10946398 with type 2 diabetes mellitus in adults: a meta-analysis. Medicine 99(30):e21383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li C, Shen K, Yang M, Yang Y, Tao W, He S et al (2021) Association between single nucleotide polymorphisms in CDKAL1 and HHEX and type 2 diabetes in Chinese population. Diabetes Metab Syndr Obes 5(13):5113–5123

    Article  Google Scholar 

  45. Trombetta M, Bonetti S, Boselli ML, Miccoli R, Trabetti E, Malerba G et al (2013) PPARG2 Pro12Ala and ADAMTS9 rs4607103 as “insulin resistance loci” and “insulin secretion loci” in Italian individuals. The GENFIEV study and the Verona newly diagnosed type 2 diabetes study (VNDS) 4. Acta Diabetol 50:401–408

    Article  CAS  PubMed  Google Scholar 

  46. Gupta V, Vinay DG, Rafiq S, Kranthikumar MV, Janipalli CS, Giambartolomei C et al (2012) Association analysis of 31 common polymorphisms with type 2 diabetes and its related traits in Indian sib pairs. Diabetologia 55:349–357

    Article  CAS  PubMed  Google Scholar 

  47. Pizzuti A, Frittitta L, Argiolas A, Baratta R, Goldfine ID, Bozzali M et al (1999) A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance. Diabetes 48(9):1881–1884

    Article  CAS  PubMed  Google Scholar 

  48. Bacci S, Ludovico O, Prudente S, Zhang YY, Di Paola R, Mangiacotti D et al (2005) The K121Q polymorphism of the ENPP1/PC-1 gene is associated with insulin resistance/atherogenic phenotypes, including earlier onset of type 2 diabetes and myocardial infarction. Diabetes 54(10):3021–3025

    Article  CAS  PubMed  Google Scholar 

  49. Stolerman ES, Manning AK, McAteer JB, Dupuis J, Fox CS, Cupples LA et al (2008) Haplotype structure of the ENPP1 Gene and nominal association of the K121Q missense single nucleotide polymorphism with glycemic traits in the Framingham Heart Study. Diabetes 57(7):1971–1977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bacci S, De Cosmo S, Prudente S, Trischitta V (2007) ENPP1 gene, insulin resistance and related clinical outcomes. Curr Opin Clin Nutr Metab Care 10(4):403–409

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by the Scientific and Technological Research Council of Turkey (213S035).

Author information

Authors and Affiliations

  1. Department of Medical Biology, Faculty of Medicine, Selcuk University, Konya, Turkey

    Hilal Arikoglu, Dudu Erkoc-Kaya & Fatma Gokturk

  2. Department of Endocrinology and Metabolic Diseases, Hisar Hospital Intercontinental, Istanbul, Turkey

    Suleyman Hilmi Ipekci

  3. Department of Statistics, Faculty of Science, Ege University, Izmir, Turkey

    Funda Iscioglu

  4. Department of Biostatistics, Faculty of Medicine, Selcuk University, Konya, Turkey

    Muslu Kazim Korez

  5. Department of Endocrinology and Metabolic Diseases, Faculty of Medicine, Selcuk University, Konya, Turkey

    Suleyman Baldane

  6. Department of Endocrinology and Metabolic Diseases, Faculty of Cerrahpasa Medicine, Istanbul University, Istanbul, Turkey

    Mustafa Sait Gonen

Authors
  1. Hilal Arikoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dudu Erkoc-Kaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suleyman Hilmi Ipekci
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fatma Gokturk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Funda Iscioglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Muslu Kazim Korez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Suleyman Baldane
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mustafa Sait Gonen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HA concept, study design, analysis, interpretation, writing manuscript. DE-K literature search, analysis, interpretation, critical review. SHI management of patients and organizing. FI collecting data, statistical analysis design. MKK statistical analysis, interpretation. FG SNP analysis. SB Collecting patient data. MSG management of patients and organizing.

Corresponding author

Correspondence to Hilal Arikoglu.

Ethics declarations

Conflict of interest

No author has a financial or proprietary interest in any part of the study.

Ethical approval

The study was approved by the Ethical Committee of the Faculty of Medicine of Selcuk University. The ethic approval number:2013/305. The guarantor Hilal Arikoglu.

Consent to participate

All patients signed an informed consent form before study participation.

Consent to publication

All authors have all participated in the design, execution, and analysis of the paper, and that they have approved the final version.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arikoglu, H., Erkoc-Kaya, D., Ipekci, S.H. et al. Type 2 diabetes is associated with the MTNR1B gene, a genetic bridge between circadian rhythm and glucose metabolism, in a Turkish population. Mol Biol Rep 48, 4181–4189 (2021). https://doi.org/10.1007/s11033-021-06431-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-06431-9

Keywords

Search

Navigation