Analysis of the association of FTO, PPARG and PPARGC1A gene polymorphisms with carbohydrate metabolism disorders

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Background. Conducting molecular and genetic studies to investigate susceptibility to multifactorial and polygenic diseases, such as type 2 diabetes melitus and pre-diabetic conditions, is of great importance for the development of personalized prevention programs and the choice of optimal treatment. Taking into account regional and ethnic features, the study of polymorphic markers of candidate genes for fat and carbohydrate metabolism has a great practical value.

Aim. To investigate associations of polymorphisms of the FTO rs9939609, PPARG rs180128, PPARGC1A rs8192678 genes with the risk of developing type 2 diabetes mellitus and pre-diabetic conditions in residents of the Republic of Tatarstan.

Material and methods. An observational single-stage single-center controlled study was conducted in patients with various disorders of carbohydrate metabolism: prediabetes (n=138) and a confirmed diagnosis of type 2 diabetes mellitus (n=134). Molecular genetic analysis of rs9939609 polymorphism of the FTO gene, rs8192678 polymorphism of the PPARGC1A gene and rs1801282 polymorphism of the PPARG gene was performed using real-time polymerase chain reaction. The distribution of patient genotypes and alleles was compared with the Russian population. Statistical data processing included nonparametric correlation analysis using Pearson’s coefficient, calculation of Student's and χ2 tests, odds ratios, arithmetic mean values and their standard deviations using “GraphPad InStat” software.

Results. The A allele of the rs9939609 polymorphism of FTO gene increases the risk of developing type 2 diabetes mellitus and early carbohydrate metabolism disorders (OR=2.73, p=0.00007 and OR=4.17; p=0.00002, respectively). The GG genotype of the rs180128 polymorphism of the PPARG gene is associated with the risk of type 2 diabetes mellitus (OR=2.77, p=0.02).

Conclusion. The expected association of the rs9939609 FTO polymorphic marker, which determines the development of insulin resistance, with the development of type 2 diabetes mellitus and the presence of early carbohydrate metabolism disorders was obtained.

Full Text

Restricted Access

About the authors

Farida V. Valeeva

Kazan State Medical University

Email: val_farida@mail.ru
ORCID iD: 0000-0001-6000-8002
SPIN-code: 2082-3980
ResearcherId: X-5363-2019

M.D., D. Sci. (Med.), Prof., Head of Depart., Depart. of Endocrinology

Russian Federation, Kazan, Russia

Kamilya B. Khasanova

Kazan State Medical University

Author for correspondence.
Email: kamilya_khasanova@mail.ru
ORCID iD: 0000-0003-1825-487X
SPIN-code: 9494-9940
ResearcherId: X-8667-2019

M.D., Assistant, Depart. of Endocrinology

Russian Federation, Kazan, Russia

Elizaveta A. Sozinova

Republican Clinical Oncological Dispansery

Email: sozinova.liza@mail.ru
ORCID iD: 0000-0002-7010-8688

M.D., doctor of clinical laboratory diagnostics

Russian Federation, Kazan, Russia

Tatyana A. Kiseleva

Kazan State Medical University

Email: tattiana@mail.ru
ORCID iD: 0000-0001-8959-093X
SPIN-code: 8159-0120
ResearcherId: X-8889-2019

M.D., Cand. Sci. (Med.), Assoc. Prof., Depart. of Endocrinology

Russian Federation, Kazan, Russia

Elena V. Valeeva

Kazan State Medical University; Republican Clinical Oncological Dispansery; Kazan Federal University

Email: vevaleeva@ya.ru
ORCID iD: 0000-0001-7080-3878

PhD-fellow, junior research assistant, Depart. of molecular genetics, central research laboratory

Russian Federation, Kazan, Russia; Kazan, Russia; Kazan, Russia

Emiliya S. Egorova

Казанский государственный медицинский университет

Email: jastspring@yandex.ru
ORCID iD: 0000-0002-6210-4660

PhD-fellow, junior research assistant, Depart. of molecular genetics, central research laboratory

Russian Federation, г. Казань, Россия

Ildus I. Ahmetov

Kazan State Medical University

Email: genoterra@mail.ru
ORCID iD: 0000-0002-6335-4020

M.D., D. Sci. (Med.), senior researcher, Depart. of molecular genetics, central research laboratory

Russian Federation, Kazan, Russia

References

  1. World Health Organization (WHO). Global status report on noncommunicable diseases 2010. Geneva, Switzerland: World Health Organization; 2011. https://www.who.int/nmh/publications/ncd_report_full_en.pdf (access date: 01.08.2021).
  2. International Diabetes Federation. IDF Diabetes Atlas. 9th ed. Brussels: International Diabetes Federation; 2019. https://diabetesatlas.org/upload/resources/material/20200302_133351_IDFATLAS9e-final-web.pdf (access date: 01.08.2021).
  3. Dedov II, Shestakova MV, Vikulova OK. Epidemiology of diabetes mellitus in Russian Federation: clinical and statistical report according to the federal diabetes registry. Diabetes mellitus. 2017;20(1):13–41. (In Russ.) doi: 10.14341/DM8664.
  4. Dedov II, Shestakova MV, Vikulova OK, Isakov MА, Zheleznyakova AV. Atlas of diabetes register in Russian Federation. Status 2018. Diabetes mellitus. 2019;22(2S):4–61. (In Russ.) doi: 10.14341/DM12208.
  5. Dedov II, Shestakova MV, Galstyan GR. The prevalence of type 2 diabetes mellitus in the adult population of Russia (NATION study). Diabetes mellitus. 2016;19(2):104–112. (In Russ.) doi: 10.14341/DM2004116-17.
  6. Glucose tolerance and mortality: comparison of WHO and ADA diagnostic criteria. The DECODE study group. Lancet. 1999; 354(9179):617–621. doi: 10.1016/S0140-6736(98)12131-1.
  7. Park KS. The search for genetic risk factors of type 2 diabetes mellitus. Diabetes Metab J. 2011;35(1):12–22. doi: 10.4093/dmj.2011.35.1.12.
  8. Ingelsson E, McCarthy MI. Human genetics of obesity and type 2 diabetes mellitus: Past, present, and future. Circ Genom Precis Med. 2018;11(6):e002090. doi: 10.1161/CIRCGEN.118.002090.
  9. Herder C, Roden M. Genetics of type 2 diabetes: pathophysiologic and clinical relevance. Eur J Clin Invest. 2011;41(6):679–692. doi: 10.1111/j.1365-2362.2010.02454.x.
  10. McCarthy MI. Genomics, type 2 diabetes, and obesity. N Engl J Med. 2010;363(24):2339–2350. doi: 10.1056/NEJMra0906948.
  11. Ali O. Genetics of type 2 diabetes. World J Diabetes. 2013;4(4):114–123. doi: 10.4239/wjd.v4.i4.114.
  12. Vujkovic M, Keaton JM, Lynch JA, Miller DR, Zhou J, Tcheandjieu C, Huffman JE, Assimes TL, Lorenz K, Zhu X, Hilliard AT, Judy RL, Huang J, Lee KM, Klarin D, Pyarajan S, Danesh J, Melander O, Rasheed A, Mallick NH, Hameed S, Qureshi IH, Afzal MN, Malik U, Jalal A, Abbas S, Sheng X, Gao L, Kaestner KH, Susztak K, Sun YV, DuVall SL, Cho K, Lee JS, Gaziano JM, Phillips LS, Meigs JB, Reaven PD, Wilson PW, Edwards TL, Rader DJ, Damrauer SM, O'Donnell CJ, Tsao PS; HPAP Consortium; Regeneron Genetics Center; VA Million Veteran Program; Chang KM, Voight BF, Saleheen D. 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;52(7):680–691. doi: 10.1038/s41588-020-0637-y.
  13. Linder K, Wagner R, Hatziagelaki E, Ketterer C, Heni M, Machicao F, Stefan N, Staiger H, Häring HU, Fritsche A. Allele summation of diabetes risk genes predicts impaired glucose tolerance in female and obese indivi¬duals. PLoS One. 2012;7(6):e38224. doi: 10.1371/journal.pone.0038224.
  14. Zyriax BC, Salazar R, Hoeppner W, Vettorazzi E, Herder C, Windler E. The association of genetic markers for type 2 diabetes with prediabetic status — cross-sectional data of a diabetes prevention trial. PLoS One. 2013;8(9):e75807. doi: 10.1371/journal.pone.0075807.
  15. Pei X, Liu L, Cai J, Wei W, Shen Y, Wang Y, Chen Y, Sun P, Imam MU, Ping Z, Fu X. Haplotype-based interaction of the PPARGC1A and UCP1 genes is associated with impaired fasting glucose or type 2 diabetes mellitus. Medicine (Baltimore). 2017;96(23):e6941. doi: 10.1097/D.0000000000006941.
  16. Choi JW, Moon S, Jang EJ, Lee CH, Park JS. Association of prediabetes-associated single nucleotide polymorphisms with microalbuminuria. PLoS One. 2017;12(2):e0171367. doi: 10.1371/journal.pone.0171367.
  17. Fazli GS, Moineddin R, Bierman AS, Booth GL. Ethnic variation in the conversion of prediabetes to diabetes among immigrant populations relative to Canadian-born residents: a population-based cohort study. BMJ Open Diabetes Res Care. 2020;8(1):e000907. doi: 10.1136/bmjdrc-2019-000907.
  18. Dedov II, Shestakova MV, Mayo-rov AYu, editors. Standards of specialized diabetes care. 10th edition. Diabetes mellitus. 2021;24(S1): 1–221. (In Russ.) doi: 10.14341/DM12802.
  19. Wheeler E, Barroso I. Genome-wide association studies and type 2 diabetes. Brief Funct Genomics. 2011;10(2):52–60. doi: 10.1093/bfgp/elr008.
  20. Hunt SE, McLaren W, Gil L, Thormann A, Schuilenburg H, Sheppard D, Parton A, Armean IM, Trevanion SJ, Flicek P, Cunningham F. Ensembl variation resources. Database. 2018;2018:bay119. doi: 10.1093/database/bay119.
  21. Baturin AK, Sorokina EJu, Pogozheva AV, Anokhina OV, Tutelyan VA. The study of FTO rs9939609-gene polymorphism in the Sverdlovsk region. Problems of nutrition. 2012;81(5):28–32. (In Russ.)
  22. Khromova NV, Rotar OP, Erina AM, Shavshin DA, Alexeeva NP, Kostareva AA, Konradi AO, Shlyakhto EV. Association of rs9939609 FTO gene polymorphism with metabolic syndrome and its components in Russian population. Arterialnaya Gipertenziya. 2013;19(4):312–319. (In Russ.) doi: 10.18705/1607-419X-2013-19-4-311-319.
  23. Saber-Ayad M, Manzoor S, El-Serafi A, Mahmoud I, Hammoudeh S, Rani A, Abusnana S, Sulaiman N. The FTO rs9939609 “A” allele is associated with impaired fasting glucose and insulin resistance in Emirati population. Gene. 2018;681:93–98. doi: 10.1016/j.gene.h.09.053.
  24. Ioannidis JP, Patsopoulos NA, Evangelou E. Heterogeneity in meta-analyses of genome-wide association investigations. PLoS One. 2007;2(9):e841. doi: 10.1371/journal.pone.0000841.
  25. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, So¬vio U, Bennett AJ, Mel-zer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Wal¬ker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316(5826):889–894. doi: 10.1126/science.1141634.
  26. Deeb SS, Fajas L, Nemoto M, Pihlajamäki J, Mykkänen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J. A ¬Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998;20(3):284–287. doi: 10.1038/3099.
  27. Kaydashev IP, Rasin AM, Shlykova OA, Gorbas IM, Smirnova IP, Petrushov AV, Rasin MS. Frequency of the Pro12Ala gene polymorphism PPARγ2 in ukrainian population and its possible role in metabolic syndrome development. Cytology and Genetics. 2007;41(5):298–302. doi: 10.3103/0095452707050076.
  28. Bondar IA, Filipenko ML, Shabelnikova OY, Sokolova EA. Association between gene PPARG RS1801282 PRO12ALA and type 2 diabetes in Novosiborsk region and other po¬pulations. The Siberian Medical Journal. 2014;29(2):75–78. (In Russ.) doi: 10.29001/2073-8552-2014-29-2-75-78.
  29. González-Sánchez JL, Serrano Ríos M, Fernández Perez C, Laakso M, Martínez Larrad MT. Effect of the ¬Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma-2 gene on adiposity, insulin sensitivity and lipid profile in the Spanish population. Eur J Endocrinol. 2002;147(4):495–501. doi: 10.1530/eje.0.1470495.
  30. Bhatt SP, Misra A, Sharma M, Luthra K, Guleria R, Pandey RM, Vikram NK. Ala/Ala genotype of Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-γ2 gene is associated with obesity and insulin resistance in Asian Indians. Diabetes Technol Ther. 2012;14(9):828–834. doi: 10.1089/dia.2011.0277.
  31. Nizamutdinov II, Korostin DO, Ilinsky VV, Rakitko AS. Criteria for the selection of genetic markers in the assessment of predisposition to multifactorial traits. Vestnik RGMU. 2016;(6):25–32. (In Russ.) doi: 10.24075/brsmu.2016-06-05.
  32. Soyal S, Krempler F, Oberkofler H, Patsch W. PGC-1alpha: a potent transcriptional cofactor involved in the pathogenesis of type 2 diabetes. Diabetologia. 2006;49(7):1477–1488. doi: 10.1007/s00125-006-0268-6.
  33. Yang Y, Mo X, Chen S, Lu X, Gu D. Association of peroxisome proliferator‐activated receptor gamma coactivator 1 alpha (PPARGC1A) gene polymorphisms and type 2 diabetes mellitus: a meta‐analysis. Diabetes Metab Res Rev. 2011;27:177–184. doi: 10.1002/dmrr.1158.
  34. Meirhaeghe A, Fajas L, Helbecque N, Cottel D, Auwerx J, Deeb SS, Amouyel P. Impact of the peroxisome proliferator activated receptor gamma2 Pro12Ala polymorphism on adiposity, lipids and non-insulin-dependent diabetes mellitus. Int J Obes Relat Metab Disord. 2000;24(2):195–199. doi: 10.1038/sj.ijo.0801112.
  35. Global'nyy doklad po dia¬betu. Zheneva: Vsemirnaya organizatsiya zdravoohraneniya; 2018. (Global report on diabetes. Geneva: World Health Organization; 2018.) https://apps.who.int/iris/bitstream/handle/10665/275388/9789244565254-rus.pdf (access date: 14.06.2021). (In Russ.)

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

© 2022 Eco-Vector