Association of adiponectin gene alleles with type 2 diabetes mellitus in residents of Bashkortostan

Type 2 diabetes mellitus (T2DM) is one of the most acute problems of the modern world. The disease is characterized by high ratio of micro- and macrovascular complications. T2DM is a multifactorial and polygenic disease, structure of hereditary predisposition to which may be population-specific.

Aim — the analysis of allelic associations of adiponectin gene (ADIPOQ, rs17366743) with T2DM, its clinical and metabolic characteristics and complications in T2DM patients resident in the Republic of Bashkortostan.

Material and methods. 3 PCR-based method of genotyping with polymorphic marker rs17366743 of ADIPOQ gene in 433 T2DM patients and 428 healthy controls, residents of Bashkortostan.

Results. The ratio of genotype CT and allele С was higher in T2DM patients compared with controls (15.7% vs. 6.8%; p=0.0002 and 7.8% vs. 3.4%; p<0.0001, respectively). Genotype ТТ and allele Т were less frequent in T2DM than in healthy subjects (84.3 and 93,2%; p=0.0002; 92.2 and 96.6%, p<0.0001, respectively). The association with the development of diabetic retinopathy and cataract was shown (p=0,044, p=0,008, respectively).

Conclusions. Allele C and genotype CT are risk markers of T2DM (OR=2.43 and 2.56 respectively).

diabetes mellitus type 2, adiponectin gene ADIPOQ, rs17366743 polymorphism, polymerase chain reaction

1. Ruan H, Dong LQ. Adiponectin signaling and function in insulin target tissues. J Mol Cell Biol. 2016;8(2):101-109. doi: https://doi.org/10.1093/jmcb/mjw014

2. Kadowaki T, Yamauchi T, Kubota N, et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116(7):1784-1792. doi: https://doi.org/10.1172/jci29126

3. Yamauchi T, Iwabu M, Okada-Iwabu M, Kadowaki T. Adiponectin receptors: a review of their structure, function and how they work. Best Pract Res Clin Endocrinol Metab. 2014;28(1):15-23. doi: https://doi.org/10.1016/j.beem.2013.09.003

4. Hui E, Xu A, Chow WS, et al. Hypoadiponectinemia as an independent predictor for the progression of carotid atherosclerosis: a 5-year prospective study. Metab Syndr Relat Disord. 2014;12(10):517-522. doi: https://doi.org/10.1089/met.2014.0024

5. Matsuzawa Y. Establishment of a concept of visceral fat syndrome and discovery of adiponectin. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(2):131-141. doi: https://doi.org/10.2183/pjab.86.131

6. Xu A, Vanhoutte PM. Adiponectin and adipocyte fatty acid binding protein in the pathogenesis of cardiovascular disease. Am J Physiol Heart Circ Physiol. 2012;302(6):H1231-H1240. doi: https://doi.org/10.1152/ajpheart.00765.2011

7. Wang Y, Zhang D, Liu Y, et al. Association study of the single nucleotide polymorphisms in adiponectin-associated genes with type 2 diabetes in Han Chinese. J Genet Genomics. 2009;36(7):417-423. doi: https://doi.org/10.1016/s1673-8527(08)60131-9

8. Warren LL, Li L, Nelson MR, et al. Deep resequencing unveils genetic architecture of ADIPOQ and identifies a novel low-frequency variant strongly associated with adiponectin variation. Diabetes. 2012;61(5):1297-1301. doi: https://doi.org/10.2337/db11-0985

9. Heid IM, Wagner SA, Gohlke H, et al. Genetic architecture of the APML gene and its influence on adiponectin plasma levels and parameters of the metabolic syndrome in 1727 healthy caucasians. Diabetes. 2006;55(2):375-384. doi: https://doi.org/10.2337/diabetes.55.02.06.db05-0747

10. Hivert MF, Manning AK, Mcateer JB, et al. Common variants in the adiponectin gene (ADIPOQ) associated with plasma adiponectin levels, type 2 diabetes, and diabetes-related quantitative traits: the Framingham Offspring Study. Diabetes. 2008;57(12):3353-3359. doi: https://doi.org/10.2337/db08-0700

11. Tsai MK, Wang HM, Shiang JC, et al. Sequence variants of ADIPOQ and association with type 2 diabetes mellitus in Taiwan Chinese Han Population. Scientific World Journal. 2014;2014:650393. doi: https://doi.org/10.1155/2014/650393

12. Du W, Li Q, Lu Y, et al. Genetic variants in ADIPOQ gene and the risk of type 2 diabetes: a case-control study of Chinese Han Population. Endocrine. 2011;40(3):413-422. doi: https://doi.org/10.1007/s12020-011-9488-8

13. Ramya K, Ayyappa KA, Ghosh S, et al. Genetic association of ADIPOQ gene variants with type 2 diabetes, obesity and serum adiponectin levels in South Indian Population. Gene. 2013;532(2):253-262. doi: https://doi.org/10.1016/j.gene.2013.09.012

14. Chu H, Wang M, Zhong D, et al. ADIPOQ polymorphisms are associated with type 2 diabetes mellitus: a metaanalysis study. Diabetes Metab Res Rev. 2013;29(7):532-545. doi: https://doi.org/10.1002/dmrr.2424

15. Han LY, Wu QH, Jiao ML, et al. Associations between single-nucleotide polymorphisms (+45t>G, +276g>T, –11377c>G, –11391g>A) of adiponectin gene and type 2 diabetes mellitus: a systematic review and metaanalysis. Diabetologia. 2011;54(9):2303-2314. doi: https://doi.org/10.1007/s00125-011-2202-9

16. Tanimura D, Shibata R, Izawa H, et al. Relation of a common variant of the adiponectin gene to serum adiponectin concentration and metabolic traits in an aged Japanese Population. Eur J Hum Genet. 2011;19(3):262-269. doi: https://doi.org/10.1038/ejhg.2010.201

17. Vasseur F. Single-nucleotide polymorphism haplotypes in the both proximal promoter and EXON 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians. Hum Mol Genet. 2002;11(21):2607-2614. doi: https://doi.org/10.1093/hmg/11.21.2607

18. Алексеева Л.Л., Игнатьев П.М., Осаковский В.Л., и др. Ассоциация полиморфных маркеров гена адипонектина с диабетической ретинопатией при сахарном диабете 2-го типа у якутов. // Якутский медицинский журнал. — 2011. — №1. — С. 37-40. [Alekseeva LL, Ignatyev PM, Osakovsky VL, et al. Association of polymorphic markers of adiponectine gene with diabetic retinopathy at type 2 diabetes mellitus in the Yakuts. Yakut Medical Journal. 2011;1:37-40. (In Russ.)].

19. Сметнев С.А., Мешков А.Н. Роль пептидных гормонов (адипонектин, лептин, инсулин) в патогенезе атеросклероза. //Рациональная фармакотерапия в кардиологии. — 2015. — Т. 11. — № 5. — С. 522-528. [Smetnev SA, Meshkov AN. The role of peptide hormones (adiponectin, leptin, insulin) in the pathogenesis of atherosclerosis. Rational Pharmacotherapy in Cardiology. 2015;11(5):522-528. (In Russ.)].

20. Бабак О.Я., Клименко Н.Н. Физиологическая и патофизиологическая роль адипонектина в комплексном регулировании обмена веществ и развитии сердечно-сосудистых заболеваний. // Украинский терапевтический журнал. — 2010. — № 2. — С. 94-100. [Babak OYa, Klimenko NN. Physiological and pathophysiological roles of adiponectin in the integrated regulation of metabolic and cardiovascular diseases. Ukrainian Therapeutic Journal. 2010;2:94-100. (In Russ.)].

21. Hotta K, Funahashi T, Bodkin NL, et al. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes. 2001;50(5):1126-1133. doi: https://doi.org/10.2337/diabetes.50.5.1126

22. Schwarz PE, Govindarajalu S, Towers W, et al. Haplotypes in the promoter region of the ADIPOQ gene are associated with increased diabetes risk in a German Caucasian Population. Horm Metab Res. 2006;38(7):447-451. doi: https://doi.org/10.1055/s-2006-947842

23. Исакова Ж.Т., Лунегова О.С., Талайбекова Э.T., и др. Ассоциация полиморфного маркера G276т гена адипонектина с развитием метаболического синдрома у пациентов киргизской национальности. // Терапевтический архив. — 2015. — Т. 87. — № 10. — С. 85-90. [Isakova ZhT, Lunegova OS, Talaibekova ET, et al. Association of adiponectin gene G276t polymorphism with the development of metabolic syndrome in ethnic Kyrgyz patients. Ter Arkh. 2015;87(10):85-90. (In Russ.)]. doi: https://doi.org/10.17116/terarkh2015871085-90

24. Ghoshal K, Bhattacharyya M. Adiponectin: probe of the molecular paradigm associating diabetes and obesity. World J Diabetes. 2015;6(1):151-166. doi: https://doi.org/10.4239/wjd.v6.i1.151

25. Rohde K, Keller M, Horstmann A, et al. Role of genetic variants in ADIPOQ in human eating behavior. Genes Nutr. 2015;10(1):449. doi: https://doi.org/10.1007/s12263-014-0449-8

26. 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: https://doi.org/10.2337/diabetes.53.2007.s31

27. 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: https://doi.org/10.2337/diabetes.51.2.536

28. 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, ADIPOR1 and ADIPOR2 genes with type 2 diabetes mellitus. Diabetes Mellitus. 2015;18(2):5-11. (In Russ.)]. doi: https://doi.org/10.14341/dm201525-11

29. 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: https://doi.org/10.1900/rds.2008.5.28

30. Filippi E, Sentinelli F, Trischitta V, et al. Association of the human adiponectin gene and insulin resistance. Eur J Hum Genet. 2004;12(3):199-205. doi: https://doi.org/10.1038/sj.ejhg.5201120