THE ROLE AND INTERACTION OF POLYMORPHIC VARIANTS OF NON-ALLELIC GENES KCNJ11, ADIPOQ, ITLN1, LEP, TCF7L2, PPARG IN THE INCREASE IN THE RISK OF DIABETES TYPE 2 IN KYRGYZ REPUBLIC

DOI: https://doi.org/10.29296/24999490-2019-04-06

Zh.T. Isakova(1), V.N. Kipen(2), E.T. Talaibekova(1), A.A. Aldashev(1), N.M. Aldasheva(1), T.M. Bectursunov(3), E.M. Mirrakhimov(4) 1-Research Institute of Molecular Biology and Medicine, Togolok-Moldo str, 3, Bishkek, 720040, Kyrgyz Republic; 2-The Institute of Genetics and Cytology of The National Academy of Sciences of Belarus, Akademicheskaya str, 27, Minsk, 220072, Republic of Belarus; 3-I.K. Akhunbaev Kyrgyz State Medical Academy, Akhunbaev str, 92, Bishkek, 720020, Kyrgyz Republic; 4-National Center of Cardiology and Internal Medicine, Togolok-Moldo str, 3, Bishkek, 720040, Kyrgyz Republic E-mail: jainagul@mail.ru

Aim. To study the intergenic interaction and estimate the contribution of polymorphic loci p.K23E (rs5219, KCNJ11), g.15661G>T (rs1501299, ADIPOQ), p.V109D (rs2274907, ITLN1), g.2453G>A (rs7799039, LEP), g.53341C>T (rs7903146, TCF7L2), and p.P12A (rs1801282, PPARG) in the gain of the risk of DM2 using bioinformatics method of multifactor dimensionality reduction (MDR). Material and methods. A study conducted by the «case-control», included 114 patients (61 male (53,5%), 53 females (46,5%)) with DM2 (main group) and 109 patients (61 male (56%), 48 females (44%)) without DM2 (control group). Genotyping was performed by the PCR-RFLP. Analysis of intergenic interactions bioinformatics was conducted by the method of multifactor dimensionality reduction (Multifactor Dimensionality Reduction, MDR). Results. Among studied polymorphic variants the largest contribution to the gain in the risk of DM2 in persons of Kyrgyz nationality is contributeв by g.15661G>T (ADIPOQ), and p.K23E (KCNJ11). Genetic markers of the elevated risk of DM2 include: allele T (OR=1,68; 95% CI=[1,09–2,60], p=0,025), the heterozygous genotype GT (OR=1,79, 95% CI=[1,05–3,05], p=0,037) of the polymorphism g.15661G>T (ADIPOQ), and allele A of the polymorphism p.K23E (KCNJ11) – OR=1,62 (95% CI=[1,10–2,38], p=0,019). Polymorphic loci p.V109D (ITLN1), g.2453G>A (LEP), g.53341C>T (TCF7L2) and p.P12A (PPARG) in the progress of DM2 do not have a significant impact individually, but the implementation in phenotypic DM2 they can take place due to the effect of intergenic interactions. In the presence of a genetic profile «CC (g.53341C>T, TCF7L2) / AG (g.2453G>A, LEP) / AA (p.K23E, KCNJ11)» and «СT (g.5341C>T, TCF7L2) / AA (g.2453G>A, LEP) / AG (p.K23E, KCNJ11)» the risk of developing DM2 increases by 5–8 times. Conclusion. For persons of Kyrgyz nationality polymorphic loci p.K23E (KCNJ11) and g.15661G>T (ADIPOQ) are associated with the increased risk of DM2. The loci g.2453G>A (LEP), p.V109D (ITLN1), g.53341C>T (TCF7L2) and p.P12A (PPARG) can affect the phenotypic realization of DM2 in combination with pathogenetically significant genotypes of the genes KCNJ11 and ADIPOQ.
Keywords: 
KCNJ11, ADIPOQ, ITLN1, LEP, TCF7L2, PPARG, gene interaction

Список литературы: 
  1. Дедов И.И. Сахарный диабет – опаснейший вызов мировому сообществу. Вестник Российской академии медицинских наук. 2012; 67 (1): 7–13. [Dedov I.I. Diabetes mellitus – a dangerous treat to the mankind. Annals of the Russian academy of medical sciences. 2012; 67 (1): 7–13 (in Russian)] https://doi.org/10.15690/vramn.v67i1.103
  2. Республиканский медико-информационный центр Министерства здравоохранения Кыргызской Республики. Бишкек, 2015. http://zdorovie.akipress.org/news:1343230 [Respublikanskiy mediko-informatsionnyy tsentr Ministerstva zdravookhraneniya Kyrgyzskoy Respubliki. Bishkek. 2015 (in Russian)]. http://zdorovie.akipress.org/news:1343230
  3. Бондарь И.А., Шабельникова О.Ю. Генетические основы сахарного диабета 2 типа. Сахарный диабет. 2013; 4: 11–6. [Bondar’ I.A, Shabel’nikova O.Yu. Genetic framework of type 2 diabetes mellitus. Diabetes mellitus. 2013; 4: 11–6 (in Russian)] https://doi.org/10.14341/DM2013411-16
  4. Singh S. Genetics of Type 2 Diabetes: Advances and Future Prospect. J Diabetes & Metabolism. 2015; 6: 4. http://dx.doi.org/10.4172/2155-6156.1000518
  5. Ходырев Д.С., Никитин А.Г., Бровкин А.Н., Лаврикова Е.Ю., Лебедева Н.О., Викулова О.К., Шамхалова М.Ш., Шестакова М.В., Носиков В.В., Аверьянов А.В.Анализ ассоциации полиморфных маркеров генов ADIPOQ, ADIPOR1и ADIPOR2 с сахарным диабетом 2 типа. Сахарный диабет. 2015; 18 (2): 5–11. [Khodyrev D.S., Nikitin A.G., Brovkin A.N., Lavrikova E.Y., Lebedeva N.O., Vikulova O.K., Shamhalova M.S., Shestakova M.V., Nosikov V.V., Averyanov A.V. Analiz assotsiatsii polimorfnykh markerov genov ADIPOQ, ADIPOR1i ADIPOR2 s sakharnym diabetom 2 tipa. Sakharnyy diabet. 2015; 18 (2): 5–11 (in Russian)]. http://dx.doi.org/10.14341/DM201525-11
  6. Potapov V.A., Chistiakov D.A., Dubinina A., Shamkhalova M.S., Shestakova M.V., Nosikov V.V. Adiponectin and adiponectin receptor gene variants in relation to type 2 diabetes and insulin resistance-related phenotypes. The review of diabetic studies: RDS. 2008; 5 (1): 28–37. https://doi.org/10.1900/RDS.2008.5.28
  7. Li Q., Chen M., Zhang R., Jiang F., Wang J., Zhou J., Bao Y., Hu Ch., Jia W. KCNJ11 E23K variant is associated with therapeutic effect of sulfonylureas in Chinese type 2 diabetic patients. Clin Exp Pharmacol Physiol. 2014; 41: 748–54. http://dx.doi.org/10.1111/1440-1681.12280
  8. Schwanstecher C., Meyer U., Schwanstecher M. K(IR)6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K(+) channels. Diabetes. 2002; 51: 875–9. https://doi.org/10.2337/diabetes.51.3.875
  9. Zhou D., Zhang D., Liu Y., Zhao T., Chen Z., Liu Zh., Yu L., Zhang Z., Xu H., He L. The E23K variation in the KCNJ11gene is associated with type 2 diabetes in Chinese and East Asian population. J. of Human Genetics. 2009; 54: 433–5. https://doi.org/10.1038/jhg.2009.54.
  10. Sakamoto Y., Inoue H., Keshavarz P., Miyawaki K., Yamaguch Y., Moritani M., Kunika K., Nakamura N., Yoshikawa T., Yasui N., Shiota H., Tanahashi T., Itakur M. 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: 781–93. https://doi.org/10.1007/s10038-007-0190-x
  11. Koo B., Cho Y., Park B., Cheong H., Shin H., Jang H., Kim S., Lee H., Park K. Polymorphisms of KCNJ11 (Kir6.2 gene) are associated with Type 2 diabetes and hypertension in the Korean population. Diabet Med. 2007; 24: 178–86. https://doi.org/10.1111/j.1464-5491.2006.02050.
  12. Потапов В.А. Поиск генетических маркеров, определяющих предрасположенность к сахарному диабету 2 типа. Автореф. канд. биол. наук. M., 2010; 24. [Potapov VA. Poisk geneticheskikh markerov, opredelyayushchikh predraspolozhennost’ k sakharnomu diabetu 2 tipa [dissertation abstract]. M., 2010; 24 (in Russian)]
  13. Gloyn A.L., Weedon M.N., Owen K.R., Turner M.J., Knight B.A., Hitman G., Walker M., Levy C.J., Sampson M., Halford S., McCarthy M.I., Hattersley A.T., Frayling T.M. Large-Scale Association Studies of Variants in Genes Encoding the Pancreatic β-Cell K ATP Channel Subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) Confirm That the KCNJ11E23K Variant Is Associated With Type 2 Diabetes. Diabetes. 2003; 52 (2): 568–72. https://doi.org/10.2337/diabetes.52.2.568
  14. Ezzidi I., Mtiraoui N., Cauchi S., Vaillant E., Dechaume A., Chaieb M., Kacem M., Almawi W., Froguel P., Mahjoub T., Vaxillaire M. Contribution of type 2 diabetes associated loci in the Arabic population from Tunisia: a case-control study. BMC Medical Genetics. 2009; 15: 10–33. https://doi.org/10.1186/1471-2350-10-33
  15. Jiang Y.D., Chuang L.M., Pei D., Lee Y.J., Wei J.N., Sung F.C., Chang T.J. 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. of Endocrinology. 2014; 983016. https://doi.org/10.1155/2014/983016.
  16. Rastegari A., Rabbani M., Sadeghi H.M., Imani E.F., Hasanzadeh A. Moazen F. Association of KCNJ11 (E23K) gene polymorphism with susceptibility to type 2 diabetes in Iranian patients. Adv Biomed Res. 2015; 6: 4:1. https://doi.org/10.4103/2277-9175.148256.
  17. Gu H.F., Abulaiti A., Ostenson C.G., Humphreys K., Wahlestedt C., Brookes A.J., Efendic S. 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 (1): 31–5. https://doi.org/10.2337/diabetes.53.2007.S31
  18. Hara K., Boutin P., Mori Y., Tobe K., Dina C., Yasuda K. Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes. 2002; 51: 536–40. https://doi.org/10.2337/diabetes.51.2.536
  19. Schäffler A., Zeitoun M., Wobser H., Buechler C., Aslanidis C., Herfarth H. 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. Cardiovascular diabetology. 2007; 6: 1–8. https://doi.org/10.1186/1475-2840-6-3.
  20. Pan H.Y., Guo L., Li Q. Changes of serum omentin-1-1 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. https://doi.org/10.1016/j.diabres.2010.01.013
  21. Исакова Ж.Т., Талайбекова Э.T., Асамбаева Д.А., Керимкулова А.С., Лунегова О.С., Алдашева Н.М., Алдашев А.А. Ассоциация полиморфного маркера Val109Asp гена оментина с абдоминальным ожирением в кыргызской популяции. Проблемы эндокринологии. 2015; 3: 3–8. [Isakova Zh.T, Talaibekova E., Asambaeva D.A. Kerimkulova A.S, Lunegova O.S. Aldasheva N.M., Aldashev A.A.. Assotsiatsiya polimorfnogo markera Val109Asp gena omentina s abdominal’nym ozhireniem v kyrgyzskoy populyatsii. Problemy endokrinologii. 2015; 3: 3–8 (in Russian)] https://doi.org/10.1434/probl20166234-8
  22. Yörük U, Yaykaşli KO, Özhan H,Memişoğullari R,Karabacak A,Bulur S,Aslantaş Y,Başar C, Kaya E. Association of omentin Val109Asp polymorphism with coronary artery disease. Anadolu Kardiyol Derg. 2014; 14 (6): 511–4. https://doi.org/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. International Journal of Biosciences. 2014; 5 (1): 429–34. http://dx.doi.org/10.12692/ijb/5.1.429-434
  24. Trakovická A., Moravčiková N., Candráková K., Kasarda R. Associations between LEP G2548A polymorphisms and lipids metabolism. Acta fytotechn zootechn. 2016; 19 (Special Issue): 75–9. http://dx.doi.org/10.15414/afz.2016.19.si.75-79
  25. Cao L., Mou S., Fang W., Gu L., Huang J., Gu A., Qian J., Ni Z. Correlational studies on insulin resistance and leptin gene polymorphisms in peritoneal dialysis. Iran J. Basic Med Sci. 2015; 18: 878–86.
  26. 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): 70–7.
  27. 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: 937–44. https://doi.org/10.5114/aoms.2015.54848
  28. Loder M.K., da Silva Xavier G., McDonald A., Rutter G.A. TCF7L2 controls insulin gene expression and insulin secretion in mature pancreatic β-cells. Biochem. Soc. Trans. 2008; 36: 357–9. https://doi.org/10.1042/BST0360357
  29. Cauchi S.E., Achhab Y., Choquet H., Dina C., Krempler F., Weitgasser R., Nejjari C., Patsch W., Chikri M., Meyre D., Froguel P. TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis. J. Mol. Med. 2007; 85: 777. https://doi.org/10.1007/s00109-007-0203-4.
  30. Никитин А.Г, Потапов В.А, Бровкин А.Н, Лаврикова Е.Ю, Ходырев Д.С, Шамхалова М.Ш, Сметанина С.А, Суплотова Л.Н, Шестакова М.В, Носиков В.В, Аверьянов А.В Ассоциация полиморфных маркеров гена TCF7L2 с сахарным диабетом типа 2. Журнал Клиническая практика. 2014; 1 (17): 4–11.
  31. [Nikitin A.G., Potapov V.A., Brovkin A.N., Lavrikova E.Yu., Khodyrev D.S., Shamhalova M.Sh., Smetanina S.A., Suplotova L.N., Shestakova M.V., Nosikov V.V., Averyanov A.V. Assotsiatsiya polimorfnykh markerov gena TCF7L2 s sakharnym diabetom tipa 2. Zhurnal Klinicheskaya praktika. 2014; 1 (17): 4–11 (in Russian)]
  32. Peng S., Zhu Y., Lü B., Xu F., Li X., Lai M. TCF7L2 gene polymorphisms and type 2 diabetes risk: a comprehensive and updated meta-analysis involving 121,174 subjects. Mutagenesis. 2013; 28 (1): 25–37.
  33. Guinan K.J. Worldwide distribution of type II diabetes associated TCF7L2 SNPs: evidence for stratification in Europe. Biochem Genet. 2012; 50: 159–79. https://doi.org/10.1007/s10528-011-9456-2
  34. Dou H., Ma E., Yin L., Jin Y., Wang H. The association between gene polymorphism of TCF7L2 and type 2 diabetes in Chinese Han population: a meta-analysis. PLoS One. 2013; 8 (3): e59495.
  35. Wang J., Hu F., Feng T., Zhao J., Yin L., Li L., Wang Y., Wang Q., Hu D. Meta-analysis of associations between TCF7L2 polymorphisms and risk of type 2 diabetes mellitus in the Chinese population. BMC Med Genet. 2013; 14: 8. https://doi.org/10.1186/1471-2350-14-8
  36. Guo T., Hanson R.L., Traurig M., Muller Y.L., Ma L., Mack J., Kobes S., Knowler W.C., Bogardus C., Baier L.J. TCF7L2 is not a major susceptibility gene for type 2 diabetes in Pima Indians: analysis of 3,501 individuals. Diabetes. 2007; 56 (12): 3082–8. https://doi.org/10.2337/db07-0621
  37. Alsmadi O., Al-Rubeaan K., Mohamed G., Alkayal F., Al-Saud H., Al-Saud N.A., Al-Daghri N., Mohammad S., Meyer B.F. Weak or no association of TCF7L2 variants with Type 2 diabetes risk in an Arab population. BMC 2008; Med Genet 9:72 https://doi.org/10.1186/1471-2350-9-72
  38. Vaccaro O., Lapice E., Monticelli A., Giacchetti M., Castaldo I., Galasso R., Pinelli M., Donnarumma G., Rivellese A.A., Cocozza S., Riccardi G. Pro12Ala polymorphism of the PPAR gamma 2 locus modulates the relationship between energy intake and body weight in type 2 diabetic patients. Diabetes Care. 2007; 30 (5): 1156–61. https://doi.org/10.2337/dc06-1153
  39. Tripathi A.K., Shukla S., Dwivedi M.K., Tripathi J.K., Chauhan U.K., Indurkar M., & Singh M. Type 2 diabetes in a central Indian population: association with PPARG2 P121A allele but not ENPP1 K121Q. Advances in Genomics and Genetics. 2013; 3: 1–9. https://doi.org/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; 4: 17–22. [Bondar’ I.A., Filipenko M.L., Shabel’nikova O.Yu., Sokolova E.A. Assotsiatsiya polimorfnykh markerov rs7903146 gena TCF7L2 i rs1801282 gena PPARG (Pro12Ala) s sakharnym diabetom 2 tipa v Novosibirskoy oblasti. Sakharnyy diabet. 2013; 4: 17–22 (in Russian)]. https://doi.org/10.14341/DM2013417-22
  41. Fu M., Chen H., Li X., Li J., Wu B., Cheng L., Cai M., Fu Z. Association of Pro12Ala variant in peroxisome proliferator-activated receptor-gamma2 gene with type 2. Chinese J. Med. Gen. 2002; 19 (3): 234–8. PMID: 12048686
  42. Pattanayak A.K., Bankura B., Balmiki N., Das T.K., Chowdhury S., Das M. Role of peroxisome proliferator-activated receptor gamma gene polymorphisms in type 2 diabetes mellitus patients of West Bengal, India. J. Diabetes Invest. 2014; 5: 188–91. https://doi.org/10.1111/jdi.12130