Gene-gene interactions and the contribution of polymorphic loci of the KCNJ11, ADIPOQ, omentin, leptin, TCF7L2 and PPARg genes to the development of type 2 diabetes mellitus in the Kyrgyz population: a case-control genetic association study using MDR analysis

Cover Page

Full Text

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

Abstract

There are many genetic loci associated with type 2 diabetes mellitus (T2DM). The genetic factors involved in the development of the T2DM can depend on the nature of genetic variation within and across different ethnic groups.

Aims — the aim of this study was to investigate the gene-gene interactions and to determine the role of the KCNJ11 (Glu23Lys), ADIPOQ (G276T), omentin (Val109Asp), leptin (G2548A), TCF7L2 (IVS3C/T), PPARg (Pro12Ala) genes in the development of type 2 diabetes mellitus (T2DM) in the Kyrgyz population using MDR analysis.

Material and methods. We examined 114 patients (53 females and 61 males; mean age, 54±7.4) with T2DM and 109 apparently healthy controls (48 females and 61 males; mean age, 50±8.4). Polymorphisms of the KCNJ11 (Glu23Lys), ADIPOQ (G276T), omentin (Val109Asp), leptin (G2548A), TCF7L2 (IVS3C/T), PPARg (Pro12Ala) genes were defined by PCR-RFLP assay.

Results. Among the six genes (KCNJ11, ADIPOQ, omentin, leptin, TCF7L2, PPARg) included in this study, the most significant contribution to the development of T2DM in the Kyrgyz population was detected for the ADIPOQ (2.17%) and KCNJ11 genes (2.01%).

The heterozygous genotype G276T (OR=1.79 CI 95% 1.05—3.05; p=0.036) and the 276T allele (OR=1.68 CI 95% 1.09—2.60; p=0.025) of the ADIPOQ gene were associated with a high risk of developing T2DM in the Kyrgyz population. The 23Lys allele of the KCNJ11 gene was significantly associated with T2DM in the Kyrgyz population (OR=1.62 CI 95% 1.10—2.38; p=0.019). The allele and genotype frequencies of the omentin (Val109Asp), leptin (G2548A), TCF7L2 (IVS3C/T), PPARg (Pro12Ala) genes did not differ between the studied groups (p>0.05).

Conclusions. In Kyrgyz population, the polymorphic loci Glu23Lys of the KCNJ11 gene, the 276T allele and genotype G276T of ADIPOQ are associated with T2DM. The omentin (Val109Asp), leptin (G2548A), TCF7L2 (IVS3C/T), and PPARg (Pro12Ala) genes alone do not have such a significant impact on the development of type 2 diabetes; they contribute to the phenotypic development of T2DM mainly due to gene-gene interactions.

Full Text

Restricted Access

About the authors

Zhainagul T. Isakova

Research Institute of Molecular Biology and Medicine

Author for correspondence.
Email: jainagul@mail.ru
ORCID iD: 0000-0002-3681-6939
SPIN-code: 2489-8031

MD, PhD

Kyrgyzstan, Bishkek

Elnura T. Talaibekova

Research Institute of Molecular Biology and Medicine

Email: elya-1209@mail.ru
ORCID iD: 0000-0002-4619-1928
SPIN-code: 5722-1198
Kyrgyzstan, Bishkek

Baktygul Zh. Zhyrgalbekova

Research Institute of Molecular Biology and Medicine

Email: happyflower7@mail.ru
ORCID iD: 0000-0003-0855-9450
SPIN-code: 6738-1297
Kyrgyzstan, Bishkek

Erkin M. Mirrakhimov

National Center of Cardiology and Internal Medicine

Email: erkmirr@gmail.com
ORCID iD: 0000-0003-2982-6108

MD, PhD, Professor

Kyrgyzstan, Bishkek

Nazira M. Aldasheva

Research Institute of Molecular Biology and Medicine; Kyrgyz-Russian Slavic University

Email: aldashev@gmail.com
ORCID iD: 0000-0002-0356-9118
SPIN-code: 2633-7587

MD, PhD

Kyrgyzstan, Bishkek

Almaz A. Aldashev

Research Institute of Molecular Biology and Medicine

Email: aldashev@gmail.com
ORCID iD: 0000-0002-4793-2206

MD, PhD, Professor

Kyrgyzstan, Bishkek

References

  1. Дедов И.И., Шестакова М.В., Андреева Е.Н., и др. Сахарный диабет: диагностика, лечение, профилактика. / Под ред. Дедова И.И., Шестаковой М.В. — М.: Медицинское Информационное Агентство; 2011. [Dedov II, Shestakova MV, Andreeva EN, et al. Sakharnyy Diabet: Diagnostika, Lechenie, Profilaktika. Moscow: Meditsinskoe Informatsionnoe Agentstvo; 2011. (In Russ.)].
  2. Султаналиева Р.Б., Сагынова С.К., Албакова А.О., и др. Эпидемиологические аспекты сахарного диабета в Кыргызстане (по данным государственного регистра сахарного диабета в разрезе 2015 г.). // Вестник КРСУ. — 2016. — Т. 16. — № 11. — С. 140—144. [Sultanalieva RB, Sagynova SK, Albakova AO, et al. Epidemiological facts of diabetes mellitus in Kyrgyzstan (the data of the National register of diabetes during 2015 Year). Vestnik KRSU. 2016;16(11):140-144. (In Russ.)].
  3. Бондарь И.А., Шабельникова О.Ю. Генетические основы сахарного диабета 2-го типа. // Сахарный диабет. — 2013. — Т. 16. — № 4. — С. 11—16. [Bondar’ IA, Shabel’nikova OYu. Genetic framework of type 2 diabetes mellitus. Diabetes Mellitus. 2013;16(4):11-16. (In Russ.)]. doi: 10.14341/Dm2013411—16
  4. Singh S. Genetics of type 2 diabetes: advances and future prospect. J Diabetes Metab. 2015;6(4):518. doi: 10.4172/2155—6156.1000518
  5. Ходырев Д.С., Никитин А.Г., Бровкин А.Н., и др. Анализ ассоциации полиморфных маркеров генов ADIPOQ, ADIPOR1 и ADIPOR2 с сахарным диабетом 2-го типа. // Сахарный диабет. — 2015. — Т. 18. — № 2. — С. 5—11. [Khodyrev DS, Nikitin AG, Brovkin AN, et al. Association of polymorphisms of the ADIPOQ, ADIPO1 and ADIPOR2 genes with type 2 diabetes mellitus. Diabetes Mellitus. 2015;18(2):5-11. (In Russ.)].doi: 10.14341/Dm201525—11
  6. Potapov VA, Chistiakov DA, Dubinina A, et al. Adiponectin and Adiponectin receptor gene variants in relation to type 2 diabetes and insulin resistance—related phenotypes. Rev Diabet Stud. 2008; 5(1):28-37. doi: 10.1900/Rds.2008.5.28
  7. Li Q, Chen M, Zhang R, et al. KCNJ11 E23K variant is associated with the therapeutic effect of sulphonylureas in chinese type 2 diabetic patients. Clin Exp Pharmacol Physiol. 2014;41(10):748-754. doi: 10.1111/1440—1681.12280
  8. Schwanstecher C, Meyer U, Schwanstecher M. Kir6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic — cell Atp—Sensitive K+ Channels. Diabetes. 2002;51(3):875-879. doi: 10.2337/Diabetes.51.3.875
  9. Zhou D, Zhang D, Liu Y, et al. The E23K variation in the KCNJ11 gene is associated with type 2 diabetes in Chinese and East Asian population. J Hum Genet. 2009;54(7):433-435.doi: 10.1038/Jhg.2009.54
  10. Sakamoto Y, Inoue H, Keshavarz P, et al. SNPS in the KCNJ11—ABCC8 gene locus are associated with type 2 diabetes and blood pressure levels in the Japanese population. J Hum Genet. 2007;52(10):781-793. doi: 10.1007/S10038—007—0190—X
  11. Koo BK, Cho YM, Park BL, et al. Polymorphisms of KCNJ11 (Kir6.2 gene) are associated with type 2 diabetes and hypertension in the Korean population. Diabet Med. 2007;24(2):178-186. doi: 10.1111/J.1464—5491.2006.02050.X
  12. Потапов В.А. Поиск генетических маркеров, определяющих предрасположенность к сахарному диабету 2-го типа: Дис. ... канд. биол. наук. — M. 2010. [Potapov VA. Poisk geneticheskikh markerov, opredelyayushchikh predraspolozhennost’ k sakharnomu diabetu 2 tipa: Diss. Moscow. 2010. (In Russ.)].
  13. Gloyn AL, Weedon MN, Owen KR, et al. Large-scale association studies of variants in genes encoding the pancreatic — cell KATP channel subunits Kir 6.2 (KCNJ11) and Sur1 (AbCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes. 2003;52(2):568-572. doi: 10.2337/Diabetes.52.2.568
  14. Ezzidi I, Mtiraoui N, Cauchi S, et al. Contribution of type 2 diabetes associated loci in the Arabic population from Tunisia: a case control study. BMC Med Genet. 2009;10:33.doi: 10.1186/1471—2350—10—33
  15. Jiang YD, Chuang LM, Pei D, et al. Genetic variations in the Kir6.2 subunit (KCNJ11) of pancreatic ATP—Sensitive potassium channel gene are associated with insulin response to glucose loading and early onset of type 2 diabetes in childhood and adolescence in Taiwan. Int J Endocrinol. 2014;2014:983016.doi: 10.1155/2014/983016
  16. Rastegari A, Rabbani M, Sadeghi HM, et al. Association of KCNJ11 (E23K) gene polymorphism with susceptibility to type 2 diabetes in Iranian patients. Adv Biomed Res. 2015;4:1.doi: 10.4103/2277—9175.148256
  17. Gu HF, Abulaiti A, Ostenson CG, et al. Single nucleotide polymorphisms in the proximal promoter region of the adiponectin (APM1) gene are associated with type 2 diabetes in Swedish caucasians. Diabetes. 2004;53(Supplement 1):S31-S35.doi: 10.2337/diabetes.53.2007.S31
  18. Hara K, Boutin P, Mori Y, et al. Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes. 2002;51(2):536-540.doi: 10.2337/diabetes.51.2.536
  19. Schaffler A, Zeitoun M, Wobser H, et al. Frequency and significance of the novel single nucleotide missense polymorphism Val109Asp in the human gene encoding omentin in caucasian patients with type 2 diabetes mellitus or chronic inflammatory bowel diseases. Cardiovasc Diabetol. 2007;6:3. doi: 10.1186/1475—2840—6—3
  20. Pan HY, Guo L, Li Q. Changes of serum omentin-1 levels in normal subjects and in patients with impaired glucose regulation and with newly diagnosed and untreated type 2 diabetes. Diabetes Res Clin Pract. 2010;88(1):29-33. doi: 10.1016/j.diabres.2010.01.013
  21. Исакова Ж.Т., Талайбекова Э.Т., Асамбаева Д.А., и др. Ассоциация полиморфного маркера Val109Asp гена оментина с абдоминальным ожирением в кыргызской популяции. // Проблемы эндокринологии. — 2016. — Т. 62. — № 3. — С. 4—8. [Isakova ZT, Talaibekova EТ, Asambaeva DA, et al. A polymorphic marker Val109Asp in the omentin gene are associated with abdominal obesity in the kyrgyz population. Problems of endocrinology. 2016;62(3):4-8. (In Russ.)]. doi: 10.14341/probl20166234—8
  22. Yoruk U, Yaykasli KO, Ozhan H, et al. Association of omentin Val109Asp polymorphism with coronary artery disease. Anadolu Kardiyol Derg. 2014;14(6):511-514. doi: 10.5152/akd.2013.4932
  23. Bahadori M, Kohan L, Farzan M, et al. An increased risk of breast cancer associated with Val109Asp polymorphism in omentin gene. Int J Biosci. 2014;5(1):429-434. doi: 10.12692/ijb/5.1.429—434
  24. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994; 372(6505):425-432. doi: 10.1038/372425a0
  25. Trakovická A, Moravčíková N, Candráková K, Kasarda R. Associations between LEP G2548A polymorphisms and lipids metabolism. Acta fytotechn zootechn. 2016;19(Special issue):75-79.doi: 10.15414/afz.2016.19.si.75—79
  26. Cao L, Mou S, Fang W, et al. Correlational studies on insulin resistance and leptin gene polymorphisms in peritoneal dialysis patients. Iran J Basic Med Sci. 2015;18(9):878-886.
  27. Kohan L, Nasiri M, Habib A, Bolhasani A. Association of G-2548A polymorphism in the promoter of leptin gene with plasma leptin level and risk of type 2 diabetes. JSSU. 2013;21(1):70-77.
  28. Motawi T, Salman T, Shaker O, Abdelhamid A. Association of polymorphism in adiponectin (+45 T/G) and leptin (–2548 G/A) genes with type 2 diabetes mellitus in male Egyptians. Arch Med Sci. 2015;11(5):937-944. doi: 10.5114/aoms.2015.54848
  29. Loder MK, da Silva Xavier G, Mcdonald A, Rutter GA. TCF7L2 controls insulin gene expression and insulin secretion in mature pancreatic β-cells. Biochem Soc Trans. 2008;36(Pt 3):357-359.doi: 10.1042/BST0360357
  30. Cauchi S, El Achhab Y, Choquet H, et al. TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global metaanalysis. J Mol Med (Berl). 2007;85(7):777-782.doi: 10.1007/s00109—007—0203—4
  31. Никитин А.Г., Потапов В.А., Бровкин А.Н., и др. Ассоциация полиморфных маркеров гена TCF7L2 с сахарным диабетом 2-го типа. // Клиническая практика. — 2014. — № 1. — C. 4—11. [Nikitin AG, Potapov VA, Brovkin AN, et al. Association of the polymorphisms of the TCF7l2 genes with type 2 diabetes. Klinicheskaya Praktika. 2014;(1):4-11. (In Russ.)].
  32. Peng S, Zhu Y, Lu B, et al. TCF7L2 gene polymorphisms and type 2 diabetes risk: a comprehensive and updated metaanalysis involving 121,174 subjects. Mutagenesis. 2013;28(1):25-37.doi: 10.1093/mutage/ges048
  33. Guinan KJ. Worldwide distribution of type ii diabetes associated TCF7L2 SNPs: evidence for stratification in Europe. Biochem Genet. 2012;50(3-4):159-179. doi: 10.1007/s10528—011—9456—2
  34. Dou H, Ma E, Yin L, et al. The association between gene polymorphism of TCF7L2 and type 2 diabetes in Chinese HAN population: a metaanalysis. PLoS One. 2013;8(3):e59495.doi: 10.1371/journal.pone.0059495
  35. Wang J, Hu F, Feng T, et al. Metaanalysis of associations between TCF7L2 polymorphisms and risk of type 2 diabetes mellitus in the Chinese population. BMC Med Genet. 2013;14:8.doi: 10.1186/1471—2350—14—8
  36. Guo T, Hanson RL, Traurig M, et al. TCF7L2 is not a major susceptibility gene for type 2 diabetes in pima indians: analysis of 3,501 individuals. Diabetes. 2007;56(12):3082-3088.doi: 10.2337/db07—0621
  37. Alsmadi O, Al-Rubeaan K, Mohamed G, et al. Weak or no association of TCF7L2 variants with type 2 diabetes risk in an Arab population. BMC Med Genet. 2008;9:72. doi: 10.1186/1471—2350—9—72
  38. Vaccaro O, Lapice E, Monticelli A, et al. Pro12Ala PPARgamma2 locus modulates the relationship between energy intake and body weight in type 2 diabetic patients. Diabetes Care. 2007;30(5):1156-1161. doi: 10.2337/dc06—1153
  39. Tripathi AK, Shukla S, Dwivedi Mk, et al. Type 2 diabetes in a central indian population: association with PPARG2 P121A allele but not ENPP1 K121Q. Adv Genomics Genet. 2013:1.doi: 10.2147/agg.s42936
  40. Бондарь И.А., Филипенко М.Л., Шабельникова О.Ю., Соколова Е.А. Ассоциация полиморфных маркеров Rs7903146 гена TCF7l2 и Rs1801282 гена PPARG (Pro12Ala) с сахарным диабетом 2 типа в Новосибирской области. // Сахарный диабет. — 2013. — Т. 16. — № 4. — С. 17—22. [Bondar’ IA, Filipenko ML, Shabel’nikova OYu, Sokolova EA. Rs7903146 variant of TCF7L2 gene and rs18012824 variant of PPARG2 gene (Pro12Ala) are associated with type 2 diabetes mellitus in novosibirsk population. Diabetes mellitus. 2013;16(4):17-22. (In Russ.)]doi: 10.14341/DM2013417—22
  41. Fu M, Chen H, Li X, et al. Association of Pro12Ala variant in peroxisome proliferator — activated receptor — gamma2 gene with type 2 diabetes mellitus. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2002;19(3):234-238.
  42. Pattanayak AK, Bankura B, Balmiki N, et al. Role of peroxisome proliferator—activated receptor gamma gene polymorphisms in type 2 diabetes mellitus patients of West Bengal (India). J Diabetes Investig. 2014;5(2):188-191. doi: 10.1111/jdi.12130

Supplementary files

Supplementary Files
Action
1. Сопроводительное письмо_2017_Бишкек

Download (180KB)
2. Fig. 1. Electrophoregram of the Glu23Lys polymorphism of the KCNJ11 gene.

Download (31KB)
3. Fig. 2. Electrophoregram of the G276T polymorphism of the ADIPOQ gene.

Download (37KB)
4. Fig. 3. Electrophoregram of Val109Asp polymorphism of omentin gene.

Download (39KB)
5. Fig. 4. Electrophoregram locus G2548A leptin gene.

Download (32KB)
6. Fig. 5. Electrophoretic separation of genotypes of the IVS3C / T polymorphic locus of the TCF7L2 gene after restriction.

Download (33KB)
7. Fig. 6. Electrophoretic separation of the genotypes of the polymorphic locus Pro12Ala PPARg gene after restriction.

Download (35KB)
8. Fig. 7. Intergenic interactions of polymorphic loci of KCNJ11 (Glu23Lys) genes, ADIPOQ (G276T), romentina (Val109Asp), leptin (G2548A), TCF7L2 (IVS3C / T) and the PPARg (Pro12Ala) gene in the formation of predisposition SD2 in the Kyrgyz population. Red indicates a high degree of synergistic interaction, orange indicates a lower degree of interaction; brown the second is an intermediate stage between joint actions and antagonism (lack of communication or independence of the effects of individual loci); green and blue - antagonism of effects with lesser and greater degree.

Download (1MB)

Statistics

Views

Abstract: 99

Remote (Russian): 46

PlumX


Copyright (c) 2021 Isakova Z.T., Talaibekova E.T., Zhyrgalbekova B.Z., Mirrakhimov E.M., Aldasheva N.M., Aldashev A.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies