T.A. KISELEVA¹, F.V. VALEEVA¹, D.R. ISLAMOVA¹, M.S. MEDVEDEVA²

 ¹Kazan State Medical University, Kazan

²City Polyclinic No. 7, Kazan

 Contact details:

Kiseleva T.A. — PhD (medicine), Associate Professor of the Department of Endocrinology

Address: 49 Butlerov St., Kazan, Russian Federation, 420012, tel.: +7-917-390-88-99, e-mail: tattiana@mail.ru

Type 2 diabetes mellitus (DM2) is a polygenic, multifactorial disease resulting from the interaction of genetic, epigenetic and environmental factors. Given the significant genetic and genomic research in this area, the role of genetic factors in the pathogenesis of DM2 is becoming increasingly clear. The review presents current information in the genetics of DM2, describes the technology of genome wide-associated system (GWAS) based on high-resolution biochips for the simultaneous analysis of thousands of genetic variants in a large number of patients. Due to the use of genome-wide studies, about 100 genes and more than 700 polymorphisms associated with T2DM have been described. The review provides a description of the most common genes and their polymorphisms (TCF7L2, KCNJ11, PPARG) identified by the GWAS method and showing a strong association with T2DM in various populations. In addition, the article notes the role of the ADRB2 gene, whose polymorphisms can also contribute to the development of carbohydrate metabolism disorders. The results of a study on the assessment of the relationship between the rs1042714 ADRB2 polymorphism and indicators of carbohydrate metabolism in different periods of life of overweight and obese women are presented.

Key words: type 2 diabetes, genetics, gene polymorphism.

REFERENCES

1. Mannino G.C., Andreozzi F., Sesti G. Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine. Diabetes Metab Res Rev, 2019, vol. 35 (3), p. 3109.
2. Dedov I.I., Shestakova M.V., Galstyan G.R. The prevalence of type 2 diabetes mellitus in the adult population of Russia (NATION study). Sakharnyy diabet, 2016, vol. 19, no. 2, pp. 104–112 (in Russ.).
3. Park K.S. The search for genetic risk factors of type 2diabetes mellitus. Diabetes Metab J, 2011, vol. 35 (1), pp. 12–22.
4. Moore A.F., Jablonski K.A., Mc Ateer J.B. et al. Extension of type 2 diabetes genome-wide association scanresults in the diabetes prevention program. Diabetes, 2008, vol. 57 (9), pp. 2503–2510.
5. Marín-Peñalver J.J., Martín-Timón I., Sevillano-Collantes C., Javier Del Cañizo-Gómez F. Update on the treatment of type 2 diabetes mellitus. World J Diabetes, 2016, vol. 7 (17), pp. 354–395.
6. Gloyn A.L., Pearson E.R., Antcliff J.F. et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med, 2004, vol. 350 (18), pp. 1838–1849.
7. Waterfield T., Gloyn A.L. Monogenic β-cell dysfunction in children: clinical phenotypes, genetic etiology and mutational pathways. Pediatr Health, 2008, no. 2, pp. 517–532.
8. Billings L.K., Florez J.C. The genetics of type 2 diabetes: what havewe learned from GWAS? Ann N Y Acad Sci, 2010, vol. 1212, pp. 59–77.
9. Mokhosoev I.M., Terent’ev A.A. Genetic polymorphism and predisposition to multifactorial diseases. Uspekhi sovremennogo estestvoznaniya, 2005, no. 12, pp. 87 (in Russ.).
10. Brunetti A., Chiefari E., Foti D. Recent advances in the molecular genetics of type 2 diabetes mellitus. World J Diabetes, 2014, vol. 5 (2), pp. 128–140.
11. Li M., Li C., Guan W. Evaluation of coverage variation of SNP chips for genome-wide association studies. Eur J Hum Genet, 2008, vol. 16 (5), pp. 635–643.
12. Voight B.F., Scott L.J., Steinthorsdottir V. et al. Twelve type 2 diabetes susceptibility lociidentified through large-scale association analysis. Nat Genet, 2010, vol. 42 (7), pp. 579–589.
13. Vujkovic M., Keaton J.M., Lynch J.A. et al. Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis. Nat Genet, 2020, vol. 52 (7), pp. 680–691.
14. Galicia-Garcia U., Benito-Vicente A., Jebari S. et al. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci, 2020, vol. 21 (17), p. 6275.
15. Avzaletdinova D.Sh., Morugova T.V., Sharipova L.F. et al. Association of polymorphic loci of predisposition to type 2 diabetes mellitus in various ethnic groups of the Russian Federation. Sakharnyy diabet, 2021, vol. 24, no. 3, pp. 262–272 (in Russ.).
16. Grant S.F.A. The TCF7L2 Locus: A Genetic Window Into the Pathogenesis of Type 1 and Type 2 Diabetes. Diabetes Care, 2019, vol. 42 (9), pp. 1624–1629.
17. Chen J., Ning C., Mu J., et al. Role of Wnt signaling pathways in type 2 diabetes mellitus. Mol Cell Biochem, 2021, vol. 476 (5), pp. 2219–2232.
18. Lorzadeh S., Kohan L., Ghavami S. et al. Autophagy and the Wnt signaling pathway: A focus on Wnt/β-catenin signaling. Biochim Biophys Acta Mol Cell Res, 2021, vol. 1868 (3), p. 118926.
19. Ametov A.S., Kamynina L.L., Akhmedova Z.G. Clinical aspects of the effectiveness of incretin therapy (wnt-pathogenetic pathway and TCF7L2 gene polymorphism). Rossiyskiy meditsinskiy zhurnal, 2016, vol. 22, no. 1, pp. 47–51 (in Russ.).
20. Yi F., Sun J., Lim G.E., et al. Cross Talk between the Insulin and Wnt Signaling Pathways: Evidence from Intestinal Endocrine L Cells. Endocrinology, 2008, vol. 149 (5), pp. 2341–2351.
21. Yi F., Brubaker P.L., Jin T. TCF-4 Mediates Cell Type-specific Regulation of Proglucagon Gene Expression by β-Catenin and Glycogen Synthase Kinase-3β. J Biol Chem, 2005, vol. 280 (2), pp. 1457–1464.
22. Gloyn A.L., Pearson E.R., Antcliff J.F., et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med, 2004, vol. 350 (18), pp. 1838–1849.
23. Yahaya T.O., Salisu T.F. A Review of Type 2 Diabetes Mellitus Predisposing Genes. Curr Diabetes Rev, 2019, vol. 16 (1), pp. 52–61.
24. Corrales P., Vidal-Puig A., Medina-Gomez G. PPARs and metabolic disorders associated with challenged adipose tissue plasticity. Int J Mol Sci, 2018, vol. 19 (7), pp. 2124.
25. Pisani D.F., Barquissau V., Chambard J.C., et al. Mitochondrial fissionis associated with UCP1 activity in human brite / beige adipocytes. Mol Metab, 2018, vol. 7, pp. 35–44.
26. Costa V., Amelia C., Katherine E., et al. Characterization of a novel polymorphism in pparg regulatory region associated with type 2diabetes and diabetic retinopathy in Italy. J Biomed Biotechnol, 2009, vol. 2009, pp. 1–7.
27. Sarpeshkar V., Bentley D.J. Adrenergic-beta (2) receptor polymorphism and athletic performance. Journal of human genetics, 2010, vol. 55 (8), pp. 479–485.
28. Shakhanova A., Aukenov N., Nurtazina A. et al. Association of polymorphism genes LPL, ADRB2, AGT and AGTR1 with risk of hyperinsulinism and insulin resistance in the Kazakh population. Biomed Rep, 2020, vol. 13 (5), p. 35.
29. Dahlman I., Arner P. Genetics of Adipose Tissue Biology. Prog Mol Biol Transl Sci, 2010, vol. 94, pp. 39–74.
30. Prior S.J., Goldberg A.P., Ryan A.S. ADRB2 haplotype is associated with glucose tolerance and insulin sensitivity in obese postmenopausal women. Obesity (Silver Spring), 2011, vol. 19 (2), pp. 396–401.