Associations of polymorphisms in the gene promoters of cytokines and matrix metalloproteinases with bone mineral density in postmenopausal type 2 diabetic women

Background. Osteoporosis and type 2 diabetes are common comorbidities in postmenopausal women. An important role in the bone remodeling over the menopausal transition can be played by cytokines and matrix metalloproteinases (MMPs). It was shown that allelic variants in polymorphic positions of the genes of cytokines and MMPs affect the expression of these molecules under normal and pathological conditions.

Aims. To examine associations between polymorphisms in the gene promoters of cytokines (TNFA, IL1B, IL4, IL6, IL10, VEGFA) and MMPs (MMP2, MMP3, MMP9) with bone mineral density (BMD) in postmenopausal women with type 2 diabetes.

Materials and methods. We studied 197 Caucasian diabetic women, from 50 to70 years of age. An examination of BMD in the spine, proximal femur and forearm was performed by DEXA. Thirteen polymorphisms in the promoters of TNFA: -238 A/G (rs361525), -308 A/G(rs1800629) and -863 C/A (rs1800630), IL1B: -31 C/T (rs1143627), IL4: -590 C/T (rs2243250), IL6: -174 C/G (rs1800795), IL10: -592 C/A (rs1800872) and -1082 A/G (rs1800896), VEGFA: -2578 C/A (rs699947) and +936 C/T (rs3025039), MMP2: -1306 C/T (rs243865), MMP3: -1171 5A/6A (rs3025058) and MMP9: -1562 C/T (rs3918242), were investigated.

Results. Seventy-three women had normal BMD, in 90 ones we revealed osteopenia, and 34 women had osteoporosis. Age, BMI and smoking were strongest predictors of BMD in multivariate regression analysis (p<0.0001, p=0.003 and p=0.01, respectively). In the additive model, C allele and CC genotype in MMP9 -1562 position were associated with low BMD (OR 2.16, p=0.0007 and OR 2.02, p=0.0008, respectively). Association of the polymorphism with BMD remained significant after adjustment for clinical risk factors (p<0.001). Twelve combinations of genotypes, associated positively with low BMD, were revealed by bioinformatic analysis (all p<0.005). The СС genotype in position -1562 of MMP9, CC genotype in position -863 of TNFA, GG genotype in position -308 of TNFA, and AA genotype in position -1082 of IL10 were the most prevalent variants in these combinations.

Conclusions. Variability in the gene promoters of cytokines and MMPs may confer individual susceptibility to osteoporosis in postmenopausal type 2 diabetic women.

diabetes mellitus, osteoporosis, postmenopause, bone density, genetic polymorphism

1. Дедов И.И., Мельниченко Г.А., Белая Ж.Е., и др. Остеопороз – от редкого симптома эндокринных болезней до безмолвной эпидемии XX-XXI века // Проблемы эндокринологии. – 2011. – Т. 57. – №1. – C. 35-45. [Dedov II, Mel’nichenko GA, Belaia ZE, et al. Osteoporosis: from a rare symptom of endocrine diseases to the tacit epidemic of XX-XXI centuries. Problems of Endocrinology. 2011;57(1):35-45 (In Russ.)] doi: 10.14341/probl201157135-45

2. Молитвословова Н.А., Галстян Г.Р. Остеопороз и сахарный диабет: современный взгляд на проблему // Сахарный диабет. – 2013. – Т. 16. – №1. – С. 57-62. [Molitvoslovova NA, Galstyan GR. Osteoporosis and diabetes mellitus: a modern viewpoint. Diabetes Mellitus. 2013;16(1):57-62. (In Russ.)] doi: 10.14341/2072-0351-3598

3. Rathmann W, Kostev K. Fracture risk in patients with newly diagnosed type 2 diabetes: a retrospective database analysis in primary care. J Diabetes Complications. 2015;29(6):766-770. doi: 10.1016/j.jdiacomp.2015.05.007

4. Kim SH, Kim YM, Yoo JS, et al. Increased risk of hip fractures in Korean patients with type 2 diabetes: a 6-year nationwide population-based study. J Bone Miner Metab. 2016;35(6):623-629. doi: 10.1007/s00774-016-0798-z

5. Schwartz AV, Vittinghoff E, Bauer DC, et al. Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. JAMA. 2011;305(21):2184-2192. doi: 10.1001/jama.2011.715

6. Ялочкина Т.О., Белая Ж.Е., Рожинская Л.Я., и др. Переломы костей при сахарном диабете 2 типа: распространенность и факторы риска // Сахарный диабет. – 2016. – Т. 19. – №5. – С. 359-365. [Yalochkina TO, Belaya ZE, Rozhnskaya LY, et al. Bone fractures in patients with type 2 diabetes mellitus: Prevalence and risk factors. Diabetes mellitus. 2016;19(5):359-365. (In Russ.)] doi: 10.14341/DM7796

7. Андреева Т.М. Травматизм в Российской Федерации на основе данных статистики // Социальные аспекты здоровья населения. – 2010. – Т. 16. – №4. – С. 2. [Andreeva TM. Traumatism in the Russian Federation on the basis of statistics data. Sotsial’nye aspekty zdorov’ya naseleniya. 2010;16(4):2. (In Russ.)]

8. Farr JN, Khosla S. Determinants of bone strength and quality in diabetes mellitus in humans. Bone. 2016;82:28-34. doi: 10.1016/j.bone.2015.07.027

9. Pietschmann P, Mechtcheriakova D, Meshcheryakova A, et al. Immunology of Osteoporosis: A Mini-Review. Gerontology. 2016;62(2):128-137. doi: 10.1159/000431091

10. Wang T, He C, Yu X. Pro-Inflammatory Cytokines: New Potential Therapeutic Targets for Obesity-Related Bone Disorders. Curr Drug Targets. 2017;18(14):1664-1675. doi: 10.2174/1389450118666170104153512

11. Pirola L, Ferraz JC. Role of pro- and anti-inflammatory phenomena in the physiopathology of type 2 diabetes and obesity. World J Biol Chem. 2017;8(2):120-128. doi: 10.4331/wjbc.v8.i2.120

12. Коненков В.И., Климонтов В.В., Мякина Н.Е., и др. Повышенная концентрация воспалительных цитокинов в сыворотке крови у больных сахарным диабетом 2-го типа с хронической болезнью почек // Терапевтический архив. – 2015. – Т. 87. – №6. – С. 45-49. [Konenkov VI, Klimontov VV, Myakina NE, et al. Increased serum concentrations of inflammatory cytokines in type 2 diabetic patients with chronic kidney disease. Ter Arkh. 2015;87(6):45-49. (In Russ.)] doi: 10.17116/terarkh201587645-49

13. Paiva KBS, Granjeiro JM. Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair. Prog Mol Biol Transl Sci. 2017;148:203-303. doi: 10.1016/bs.pmbts.2017.05.001

14. Paiva KB, Granjeiro JM. Bone tissue remodeling and development: focus on matrix metalloproteinase functions. Arch Biochem Biophys. 2014;561:74-87. doi: 10.1016/j.abb.2014.07.034

15. Шевченко А.В., Коненков В.И., Прокофьев В.Ф., и др. Конституциональные основы уровней спонтанной и индуцированной продукции цитокинов TNA-A, IL-1β, IL-4, IL-6 и IL-10 у здоровых лиц европеоидного населения России // Иммунология. – 2016. – Т. 37. – №5. – С. 232-238. [Shevchenko AV, Konenkov VI, Prokofiev VF, et al. Constitutional basis of the levels of spontaneous and induced production of cytokines TNA-a, IL-1β, IL-4, IL-6 and IL-10 in healthy individuals of the european population of Russia. Immunologiia. 2016;37(5):232-238. (In Russ.)] doi: 10.18821/0206-4952-2016-37-5-232-238

16. Papageorgiou N, Tousoulis D, Hatzis G, et al. Genetic Variability of Matrix Metalloproteinase Genes in Cardiovascular Disease. Curr Top Med Chem. 2012;12(10):1206-1213. doi: 10.2174/1568026611208011206

17. Tyan NV, Klimontov VV, Shevchenko AV, et al. Polymorphisms in the gene promoters of IL4, IL6, IL10 and TNFA associated with serum levels of cytokines in type 2 diabetic subjects. Diabetologia. 2016;59(S1):513.

18. Климонтов В.В, Тян Н.В., Орлов Н.Б., и др. Взаимосвязь уровня фактора роста эндотелия сосудов в сыворотке крови и полиморфизма гена VEGFA с ишемической болезнью сердца у больных сахарным диабетом 2 типа // Кардиология. – 2017. – Т. 57. – №5. – С. 17-22. [Klimontov VV, Tyan NV, Orlov NB, et al. Association of serum levels and gene polymorphism of vascular endothelium growth factor with coronary artery disease in type 2 diabetic patients. Cardiology. 2017;57(5):17-22. (In Russ.)] doi: 10.18565/cardio.2017.5.17-22

19. Ihaka R, Gentleman R. R: A Language for Data Analysis and Graphics. J Comput Graph Stat. 1996;5(3):299-314. doi: 10.1080/10618600.1996.10474713

20. Medina-Gomez C, Chesi A, Heppe DH, et al. BMD Loci Contribute to Ethnic and Developmental Differences in Skeletal Fragility across Populations: Assessment of Evolutionary Selection Pressures. Mol Biol Evol. 2015;32(11):2961-2972. doi: 10.1093/molbev/msv170

21. phgkb.cdc.gov [Internet]. Public Health Genomics Knowledge Base (v2.1). [updated 2018 Feb 23; cited 2018 Feb 25]. Available from: https://phgkb.cdc.gov/PHGKB/phenoPedia.action?firstQuery=Osteoporosis,Postmenopausal&cuiID=C0029458&typeSubmit=GO&check=y&which=2&pubOrderType=pubD.

22. Hsu YH, Kiel DP. Clinical review: Genome-wide association studies of skeletal phenotypes: what we have learned and where we are headed. J Clin Endocrinol Metab. 2012;97(10):E1958-1977. doi: 10.1210/jc.2012-1890

23. Qin L, Liu Y, Wang Y, et al. Computational Characterization of Osteoporosis Associated SNPs and Genes Identified by Genome-Wide Association Studies. PLoS One. 2016;11(3):e0150070. doi: 10.1371/journal.pone.0150070

24. Toti P, Sbordone C, Martuscelli R, et al. Gene clustering analysis in human osteoporosis disease and modifications of the jawbone. Arch Oral Biol. 2013;58(8):912-929. doi: 10.1016/j.archoralbio.2013.02.013

25. Кочеткова Е.А., Угай Л.Г., Майстровская Ю.В., и др. Роль матриксной металлопротеиназы-9 в патогенезе остеопороза у пациентов с хронической обструктивной болезнью легких // Терапевтический архив. – 2012. – Т. 84. – №8. – С. 37-40. [Kochetkova EA, Ugaĭ LG, Maistrovskaya YV, et al. Role of matrix metalloproteinase-9 in the pathogenesis of osteoporosis in patients with chronic obstructive pulmonary disease. Ter Arkh. 2012;84(8):37-40. (In Russ.)]

26. Aiken A, Khokha R. Unraveling metalloproteinase function in skeletal biology and disease using genetically altered mice. Biochim Biophys Acta. 2010;1803(1):121-132. doi: 10.1016/j.bbamcr.2009.07.002

27. Winkler C, Krumsiek J, Lempainen J, et al. A strategy for combining minor genetic susceptibility genes to improve prediction of disease in type 1 diabetes. Genes Immun. 2012;13(7):549-555. doi: 10.1038/gene.2012.36

28. Knuppel S, Meidtner K, Arregui M, et al. Joint effect of unlinked genotypes: application to type 2 diabetes in the EPIC-Potsdam case-cohort study. Ann Hum Genet. 2015;79(4):253-263. doi: 10.1111/ahg.12115

29. Коненков В.И., Шевченко А.В., Прокофьев В.Ф., и др. Ассоциации вариантов гена фактора роста сосудистого эндотелия (VEGF) и генов цитокинов (IL1В, IL4, IL6, IL10, TNFA) c сахарным диабетом 2 типа у женщин // Сахарный диабет. – 2012. – Т. 15. – №3. – С. 4-10. [Konenkov VI, Shevchenko AV, Prokof’ev VF, et al. Associations of vascular endothelial growth factor (VEGF) gene and cytokine (IL1B, IL4, IL6, IL10, TNFA) genes combinations with type 2 diabetes mellitus in women. Diabetes Mellitus 2012;15(3):4-10. (In Russ.)] doi: 10.14341/2072-0351-6079

30. Коненков В.И., Шевченко А.В., Прокофьев В.Ф., и др. Генетические факторы индукции нарушений регуляции ангиогенеза у больных сахарным диабетом 2 типа // Медицинская иммунология. – 2012. – Т. 14. – №6. – С. 489-500. [Коnenkov VI, Shevchenko AV, Prokof’ev VF, et al. Genetic factors inducing disturbed regulation of angiogenesis in diabetes mellitus type 2. Meditsinskaia immunologiia. 2012;14(6):489-500. (In Russ.)] doi: 10.15789/1563-0625-2012-6-489-500