Альманах клинической медицины. 2016; 44: 414-421
ИЗУЧЕНИЕ АССОЦИАЦИИ ПОЛИМОРФИЗМА RS5219 ГЕНА KCNJ11 С РИСКОМ РАЗВИТИЯ САХАРНОГО ДИАБЕТА 2-ГО ТИПА
https://doi.org/10.18786/2072-0505-2016-44-4-414-421Аннотация
Актуальность. Сахарный диабет (СД) 2-го типа составляет 90–95% всех случаев СД, как правило, развивается у людей старше 40 лет, страдающих ожирением, отличается высокой распространенностью, заболеваемостью и смертностью от осложнений, в первую очередь со стороны сердечно-сосудистой системы. Риск развития СД 2-го типа определяется совместным действием генетических и средовых факторов. Идентифицированы гены, ассоциированные с СД 2-го типа, к ним относится ген АТФ-зависимого калиевого канала (KCNJ11), распространенность полиморфизма которого имеет региональные особенности. Цель – изучение ассоциации полиморфизма rs5219 гена KCNJ11 с риском развития СД 2-го типа у жителей Московского региона.
Материал и методы. Обследованы 1050 человек, из них 311 мужчин и 739 женщин. СД 2-го типа имели 139 человек (17 мужчин и 122 женщины). Генотипирование полиморфизма rs5219 гена KCNJ11 проводили с применением аллель-специфичной амплификации с детекцией результатов в режиме реального времени и использованием TaqMan- зондов, комплементарных полиморфным участкам дезоксирибонуклеиновой кислоты.
Результаты. Анализ частоты встречаемости полиморфизма rs5219 гена KCNJ11 показал, что 14,2% обследованных имели генотип ТТ, 44,8% – генотип СТ, 41,1% – нормальный (дикий) генотип СС. Распространенность мутантного аллеля Т составляла 36,6%, аллеля С – 63,4%. Частота встречаемости мутантного аллеля Т статистически значимо не отличалась у об- следованных с ожирением (индекс массы тела≥30 кг/м²) от обследованных с индексом массы тела<30 кг/м² (38,8% против 35,7%), отношение шансов (ОШ) 1,14, 95% доверительный интервал (ДИ) 0,907–1,439; p=0,26. Вместе с тем величина энерготрат в покое, рассчитанная на 1 кг мышечной массы тела, была достоверно ниже у мужчин, имеющих полиморфизм rs5219 гена KCNJ11, как при гомо-, так и при гетерозиготном типе. Частота встречаемости аллеля Т и генотипа ТТ у пациентов с СД 2-го типа была выше, чем в группе сравнения. Выявлена ассоциация генотипа ТТ с риском развития СД 2-го типа (ОШ 2,35, 95% ДИ 1,018–5,43; p=0,04).
Заключение. У жителей Московского региона полиморфизм rs5219 гена KCNJ11 (аллель ри- ска Т) вносит свой вклад (наиболее выраженный и статистически значимый при гомозиготном носительстве аллеля Т) в риск развития СД 2-го типа.
Список литературы
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11. Bennett K, James C, Hussain K. Pancreatic β-cell KATP channels: Hypoglycaemia and hyperglycaemia. Rev Endocr Metab Disord. 2010;11(3):157–63. doi: 10.1007/s11154-010-9144-2.
12. Mao H, Li Q, Gao S. Meta-analysis of the relationship between common type 2 diabetes risk gene variants with gestational diabetes mellitus. PLoS One. 2012;7(9):e45882. doi: 10.1371/journal.pone.0045882.
13. Ali O. Genetics of type 2 diabetes. World J Diabetes. 2013;4(4):114–23. doi: 10.4239/wjd.v4.i4.114.
14. Qiu L, Na R, Xu R, Wang S, Sheng H, Wu W, Qu Y. Quantitative assessment of the effect of KCNJ11 gene polymorphism on the risk of type 2 diabetes. PLoS One. 2014;9(4):e93961. doi: 10.1371/journal.pone.0093961.
15. Qin LJ, Lv Y, Huang QY. Meta-analysis of association of common variants in the KCNJ11-ABCC8 region with type 2 diabetes. Genet Mol Res. 2013;12(3):2990–3002. doi: 10.4238/2013. August.20.1.
16. Cejková P, Novota P, Cerná M, Kolostová K, Nováková D, Kucera P, Novák J, Andel M, Weber P, Zdárský E. KCNJ11 E23K polymorphism and diabetes mellitus with adult onset in Czech patients. Folia Biol (Praha). 2007;53(5):173–5.
17. Lyssenko V, Jonsson A, Almgren P, Pulizzi N, Isomaa B, Tuomi T, Berglund G, Altshuler D, Nilsson P, Groop L. Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med. 2008;359(21):2220–32. doi: 10.1056/NEJMoa0801869.
18. Cauchi S, Nead KT, Choquet H, Horber F, Potoczna N, Balkau B, Marre M, Charpentier G, Froguel P, Meyre D. The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies. BMC Med Genet. 2008;9:45. doi: 10.1186/1471-2350-9-45.
19. Takeuchi F, Serizawa M, Yamamoto K, Fujisawa T, Nakashima E, Ohnaka K, Ikegami H, Sugiyama T, Katsuya T, Miyagishi M, Nakashima N, Nawata H, Nakamura J, Kono S, Takayanagi R, Kato N. Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population. Diabetes. 2009;58(7):1690–9. doi: 10.2337/db08-1494.
20. Alsmadi O, Al-Rubeaan K, Wakil SM, Imtiaz F, Mohamed G, Al-Saud H, Al-Saud NA, Aldaghri N, Mohammad S, Meyer BF. Genetic study of Saudi diabetes (GSSD): significant association of the KCNJ11 E23K polymorphism with type 2 diabetes. Diabetes Metab Res Rev. 2008;24(2):137–40. doi: 10.1002/dmrr.777.
21. Ezzidi I, Mtiraoui N, Cauchi S, Vaillant E, Dechaume A, Chaieb M, Kacem M, Almawi WY, Froguel P, Mahjoub T, Vaxillaire M. 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.
22. Koo BK, Cho YM, Park BL, Cheong HS, Shin HD, Jang HC, Kim SY, Lee HK, Park KS. Polymorphisms of KCNJ11 (Kir6.2 gene) are associated with Type 2 diabetes and hypertension in the Korean population. Diabet Med. 2007;24(2):178–86. doi: 10.1111/j.1464-5491.2006.02050.x.
23. Sakamoto Y, Inoue H, Keshavarz P, Miyawaki K, Yamaguchi Y, Moritani M, Kunika K, Nakamura N, Yoshikawa T, Yasui N, Shiota H, Tanahashi T, Itakura 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(10):781–93. doi: 10.1007/s10038-007-0190-x.
24. Hu C, Zhang R, Wang C, Wang J, Ma X, Lu J, Qin W, Hou X, Wang C, Bao Y, Xiang K, Jia W. PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 are associated with type 2 diabetes in a Chinese population. PLoS One. 2009;4(10):e7643. doi: 10.1371/journal.pone.0007643.
25. Wang F, Han XY, Ren Q, Zhang XY, Han LC, Luo YY, Zhou XH, Ji LN. Effect of genetic variants in KCNJ11, ABCC8, PPARG and HNF4A loci on the susceptibility of type 2 diabetes in Chinese Han population. Chin Med J (Engl). 2009;122(20):2477–82.
26. Zhou D, Zhang D, Liu Y, Zhao T, Chen Z, Liu Z, Yu L, Zhang Z, Xu H, He L. 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):433–5. doi: 10.1038/jhg.2009.54.
27. Wen J, Rönn T, Olsson A, Yang Z, Lu B, Du Y, Groop L, Ling C, Hu R. Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and TCF7L2 as susceptibility genes in a Han Chinese cohort. PLoS One. 2010;5(2):e9153. doi: 10.1371/journal.pone.0009153.
28. Cheung CY, Tso AW, Cheung BM, Xu A, Fong CH, Ong KL, Law LS, Wat NM, Janus ED, Sham PC, Lam KS. The KCNJ11 E23K polymorphism and progression of glycaemia in Southern Chinese: a long-term prospective study. PLoS One. 2011;6(12):e28598. doi: 10.1371/journal.pone.0028598.
29. Danquah I, Othmer T, Frank LK, Bedu-Addo G, Schulze MB, Mockenhaupt FP. The TCF7L2 rs7903146 (T) allele is associated with type 2 diabetes in urban Ghana: a hospital-based case-control study. BMC Med Genet. 2013;14:96. doi: 10.1186/1471-2350-14-96.
30. Gamboa-Meléndez MA, Huerta-Chagoya A, Moreno-Macías H, Vázquez-Cárdenas P, Ordóñez-Sánchez ML, Rodríguez-Guillén R, Riba L, Rodríguez-Torres M, Guerra-García MT, Guillén-Pineda LE, Choudhry S, Del Bosque-Plata L, Canizales-Quinteros S, Pérez-Ortiz G, Escobedo-Aguirre F, Parra A, Lerman-Garber I, Aguilar-Salinas CA, Tusié-Luna MT. Contribution of common genetic variation to the risk of type 2 diabetes in the Mexican Mestizo population. Diabetes. 2012;61(12):3314–21. doi: 10.2337/db11-0550.
31. Gupta V, Khadgawat R, Ng HK, Kumar S, Aggarwal A, Rao VR, Sachdeva MP. A validation study of type 2 diabetes-related variants of the TCF7L2, HHEX, KCNJ11, and ADIPOQ genes in one endogamous ethnic group of north India. Ann Hum Genet. 2010;74(4):361–8. doi: 10.1111/j.1469-1809.2010.00580.x.
32. Chauhan G, Spurgeon CJ, Tabassum R, Bhaskar S, Kulkarni SR, Mahajan A, Chavali S, Kumar MV, Prakash S, Dwivedi OP, Ghosh S, Yajnik CS, Tandon N, Bharadwaj D, Chandak GR. Impact of common variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the risk of type 2 diabetes in 5,164 Indians. Diabetes. 2010;59(8):2068–74. doi: 10.2337/db09-1386.
Almanac of Clinical Medicine. 2016; 44: 414-421
EVALUATION OF AN ASSOCIATION BETWEEN RS5219 POLYMORPHISM OF KCNJ11 GENE AND THE RISK OF TYPE 2 DIABETES MELLITUS
https://doi.org/10.18786/2072-0505-2016-44-4-414-421Abstract
Background: Type 2 diabetes mellitus (T2DM) represents from 90 to 95% of all diabetes and usually occurs in obese individuals above 40 years of age, is highly prevalent, associated with high morbidity and mortality from complications involving, first of all, the cardiovascular system. The risk of T2DM is determined by combined effects of genetic and environmental factors. Genes associated with T2DM have been identified, including the gene of ATPdependent potassium channel (KCNJ11); the prevalence of its polymorphisms may have some regional characteristics.
Aim: To study an association between rs5219 KCNJ11 gene polymorphisms and the risk of T2DM in the population of the Moscow Region.
Materials and methods: The study involved 1050 subjects, including 311 men and 739 women, 139 of whom (17 men and 122 women) had T2DM. Genotyping of rs5219 KCNJ11 gene polymorphisms was performed with the use of allele-specific amplification, the real-time detection and TaqMan-probes complementary to the DNA polymorphism sites.
Results: The analysis of rs5219 KCNJ11 polymorphism frequencies showed that 14.2% of patients had TT genotype, 44.8 – CT genotype, and 41.1% – normal (wild) CC genotype. The prevalence of the mutant T allele was 36.6%, that of the C allele – 63.4%. The frequency of the mutant T allele in patients with obesity (body mass index≥30 kg/m²) was not significantly different from that in patients without obesity (body mass index<30 kg/m²) (38.8% and 35.7%, respectively, odds ratio (OR) 1.14, 95% confidence interval (CI) 0.907–1.439, p=0.26). At the same time, energy expenditure at rest per kg of lean body mass was significantly lower in men who have rs5219 KCNJ11 gene polymorphism, both in homoand heterozygotes. The frequency of the T allele and TT genotype in diabetic patients was higher than in the control group. An association between TT genotype and the risk of T2DM was found (OR 2.35, CI 1.018–5.43, p=0.04).
Conclusion: In the population of the Moscow Region, gene polymorphism rs5219 KCNJ11 contributes to the risk of developing T2DM which is most obvious and statistically significant in homozygotes.
References
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2. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87(1):4–14. doi: 10.1016/j.diabres.2009.10.007.
3. McCarthy MI. Genomics, type 2 diabetes, and obesity. N Engl J Med. 2010;363(24):2339–50. doi: 10.1056/NEJMra0906948.
4. Vimaleswaran KS, Loos RJ. Progress in the genetics of common obesity and type 2 diabetes. Expert Rev Mol Med. 2010;12:e7. doi: 10.1017/S1462399410001389.
5. Wang CP, Chung FM, Shin SJ, Lee YJ. Congenital and environmental factors associated with adipocyte dysregulation as defects of insulin resistance. Rev Diabet Stud. 2007;4(2):77–84. doi: 10.1900/RDS.2007.4.77.
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13. Ali O. Genetics of type 2 diabetes. World J Diabetes. 2013;4(4):114–23. doi: 10.4239/wjd.v4.i4.114.
14. Qiu L, Na R, Xu R, Wang S, Sheng H, Wu W, Qu Y. Quantitative assessment of the effect of KCNJ11 gene polymorphism on the risk of type 2 diabetes. PLoS One. 2014;9(4):e93961. doi: 10.1371/journal.pone.0093961.
15. Qin LJ, Lv Y, Huang QY. Meta-analysis of association of common variants in the KCNJ11-ABCC8 region with type 2 diabetes. Genet Mol Res. 2013;12(3):2990–3002. doi: 10.4238/2013. August.20.1.
16. Cejková P, Novota P, Cerná M, Kolostová K, Nováková D, Kucera P, Novák J, Andel M, Weber P, Zdárský E. KCNJ11 E23K polymorphism and diabetes mellitus with adult onset in Czech patients. Folia Biol (Praha). 2007;53(5):173–5.
17. Lyssenko V, Jonsson A, Almgren P, Pulizzi N, Isomaa B, Tuomi T, Berglund G, Altshuler D, Nilsson P, Groop L. Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med. 2008;359(21):2220–32. doi: 10.1056/NEJMoa0801869.
18. Cauchi S, Nead KT, Choquet H, Horber F, Potoczna N, Balkau B, Marre M, Charpentier G, Froguel P, Meyre D. The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies. BMC Med Genet. 2008;9:45. doi: 10.1186/1471-2350-9-45.
19. Takeuchi F, Serizawa M, Yamamoto K, Fujisawa T, Nakashima E, Ohnaka K, Ikegami H, Sugiyama T, Katsuya T, Miyagishi M, Nakashima N, Nawata H, Nakamura J, Kono S, Takayanagi R, Kato N. Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population. Diabetes. 2009;58(7):1690–9. doi: 10.2337/db08-1494.
20. Alsmadi O, Al-Rubeaan K, Wakil SM, Imtiaz F, Mohamed G, Al-Saud H, Al-Saud NA, Aldaghri N, Mohammad S, Meyer BF. Genetic study of Saudi diabetes (GSSD): significant association of the KCNJ11 E23K polymorphism with type 2 diabetes. Diabetes Metab Res Rev. 2008;24(2):137–40. doi: 10.1002/dmrr.777.
21. Ezzidi I, Mtiraoui N, Cauchi S, Vaillant E, Dechaume A, Chaieb M, Kacem M, Almawi WY, Froguel P, Mahjoub T, Vaxillaire M. 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.
22. Koo BK, Cho YM, Park BL, Cheong HS, Shin HD, Jang HC, Kim SY, Lee HK, Park KS. Polymorphisms of KCNJ11 (Kir6.2 gene) are associated with Type 2 diabetes and hypertension in the Korean population. Diabet Med. 2007;24(2):178–86. doi: 10.1111/j.1464-5491.2006.02050.x.
23. Sakamoto Y, Inoue H, Keshavarz P, Miyawaki K, Yamaguchi Y, Moritani M, Kunika K, Nakamura N, Yoshikawa T, Yasui N, Shiota H, Tanahashi T, Itakura 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(10):781–93. doi: 10.1007/s10038-007-0190-x.
24. Hu C, Zhang R, Wang C, Wang J, Ma X, Lu J, Qin W, Hou X, Wang C, Bao Y, Xiang K, Jia W. PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 are associated with type 2 diabetes in a Chinese population. PLoS One. 2009;4(10):e7643. doi: 10.1371/journal.pone.0007643.
25. Wang F, Han XY, Ren Q, Zhang XY, Han LC, Luo YY, Zhou XH, Ji LN. Effect of genetic variants in KCNJ11, ABCC8, PPARG and HNF4A loci on the susceptibility of type 2 diabetes in Chinese Han population. Chin Med J (Engl). 2009;122(20):2477–82.
26. Zhou D, Zhang D, Liu Y, Zhao T, Chen Z, Liu Z, Yu L, Zhang Z, Xu H, He L. 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):433–5. doi: 10.1038/jhg.2009.54.
27. Wen J, Rönn T, Olsson A, Yang Z, Lu B, Du Y, Groop L, Ling C, Hu R. Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and TCF7L2 as susceptibility genes in a Han Chinese cohort. PLoS One. 2010;5(2):e9153. doi: 10.1371/journal.pone.0009153.
28. Cheung CY, Tso AW, Cheung BM, Xu A, Fong CH, Ong KL, Law LS, Wat NM, Janus ED, Sham PC, Lam KS. The KCNJ11 E23K polymorphism and progression of glycaemia in Southern Chinese: a long-term prospective study. PLoS One. 2011;6(12):e28598. doi: 10.1371/journal.pone.0028598.
29. Danquah I, Othmer T, Frank LK, Bedu-Addo G, Schulze MB, Mockenhaupt FP. The TCF7L2 rs7903146 (T) allele is associated with type 2 diabetes in urban Ghana: a hospital-based case-control study. BMC Med Genet. 2013;14:96. doi: 10.1186/1471-2350-14-96.
30. Gamboa-Meléndez MA, Huerta-Chagoya A, Moreno-Macías H, Vázquez-Cárdenas P, Ordóñez-Sánchez ML, Rodríguez-Guillén R, Riba L, Rodríguez-Torres M, Guerra-García MT, Guillén-Pineda LE, Choudhry S, Del Bosque-Plata L, Canizales-Quinteros S, Pérez-Ortiz G, Escobedo-Aguirre F, Parra A, Lerman-Garber I, Aguilar-Salinas CA, Tusié-Luna MT. Contribution of common genetic variation to the risk of type 2 diabetes in the Mexican Mestizo population. Diabetes. 2012;61(12):3314–21. doi: 10.2337/db11-0550.
31. Gupta V, Khadgawat R, Ng HK, Kumar S, Aggarwal A, Rao VR, Sachdeva MP. A validation study of type 2 diabetes-related variants of the TCF7L2, HHEX, KCNJ11, and ADIPOQ genes in one endogamous ethnic group of north India. Ann Hum Genet. 2010;74(4):361–8. doi: 10.1111/j.1469-1809.2010.00580.x.
32. Chauhan G, Spurgeon CJ, Tabassum R, Bhaskar S, Kulkarni SR, Mahajan A, Chavali S, Kumar MV, Prakash S, Dwivedi OP, Ghosh S, Yajnik CS, Tandon N, Bharadwaj D, Chandak GR. Impact of common variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the risk of type 2 diabetes in 5,164 Indians. Diabetes. 2010;59(8):2068–74. doi: 10.2337/db09-1386.
