设为首页 加入收藏 期刊导航 网站地图

Advances in Clinical Medicine
Vol. 13  No. 06 ( 2023 ), Article ID: 67135 , 5 pages
10.12677/ACM.2023.1361310

Cdkal1基因多态性与2型糖尿病易感性研究 相关进展

毛新玲，马生花*

青海大学附属医院内分泌科，青海 西宁

收稿日期：2023年5月13日；录用日期：2023年6月8日；发布日期：2023年6月15日

摘要

种族性或民族性是众所周知的影响糖尿病发生发展的重要因素。验证2型糖尿病(T2DM)易感基因CDKAL1 (CDK5调节亚基相关蛋白1类似物1)位点与民族、种族的关联性，为本地区少数民族易感人群的筛选和疾病分子分型提供基础。选取近5年相关文献分析CDKAL1基因及不同基因位点在T2DM不同人群中的相关性，进一步了解CDKAL1基因单核苷酸多态性(SNPs)与2型糖尿病风险之间存在的关联。

关键词

2型糖尿病，Cdkal1，基因多态性，民族

Advances in the Study of Cdkal1 Gene Polymorphisms Related to Susceptibility to Type 2 Diabetes

Xinling Mao, Shenghua Ma*

Department of Endocrinology, Affiliated Hospital of Qinghai University, Xining Qinghai

Received: May 13th, 2023; accepted: Jun. 8th, 2023; published: Jun. 15th, 2023

ABSTRACT

Ethnicity or nationality is known to be an important factor influencing the development of diabetes mellitus. To validate the association of CDKAL1 (CDK5 regulatory subunit-associated protein 1 analogue 1) locus with ethnicity and race in type 2 diabetes mellitus (T2DM) susceptibility gene, to provide a basis for screening and molecular typing of disease in susceptible populations of ethnic minorities in our region, we selected relevant literature in the past 5 years to analyze the correlation between CDKAL1 gene and different loci in different populations of T2DM, and to further understand the association between single nucleotide polymorphisms (SNPs) of CDKAL1 gene and the risk of type 2 diabetes.

Keywords:Type 2 Diabetes Mellitus, Cdkal1, Gene Polymorphism, Ethnicity

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

糖尿病(diabetes mellitus, DM)是由多种病因引起的代谢紊乱疾病，其特点是慢性高血糖，并伴有胰岛素分泌不足和(或)作用障碍，导致碳水化合物、脂肪、蛋白质代谢紊乱，造成多种器官的慢性损伤、功能障碍衰竭。由环境因素和遗传因素共同作用所导致的2型糖尿病(T2DM)在世界范围内的患病率正不断增加 [1] 。由于现在生活水平提高，饮食结构不合理，体力活动减少，人口老龄化等原因，糖尿病的发病率越来越高。据估计，2017年全球有4.51亿(18~99岁)糖尿病患者。到2045年，这些数字预计将增加到6.93亿 [2] 。

在遗传因素方面，Cdkal1 (CDK5 regulatory subunit associated protein 1-like 1)基因的变异与不同种族人群的胰岛素反应受损和T2D风险增加有关 [1] ，2007年全基因组研究发现Cdkal1基因是人类T2DM重要的风险基因之一 [3] 。

2. Cdkal1影响胰岛素分泌的机制

1) CDK5介导途径 Cdkal1在人类胰岛、大脑和骨骼中高度表达，Cdkal1经过转录、翻译、剪接后的蛋白质与CDK5 (细胞周期依赖蛋白激酶5)活性抑制物CDK5RAP1 (CDK5调节亚单位相关蛋白1)结构域高度相似，因此Cdkal1表达的蛋白质也可以与CDK5结合，发挥抑制的作用。通过逆转录聚合酶链反应、免疫细胞化学和蛋白质印迹证明Cdk5存在于分泌胰岛素的胰腺β细胞中，是一种丝氨酸/苏氨酸蛋白激酶。葡萄糖刺激胰岛素反应性分泌会被CDK5抑制，而这一结合过程保护了胰岛免受因葡萄糖浓度升高而引起的胰岛功能障碍。其机制可能是：a) 电压门控Ca2+通道 胰岛β细胞的葡萄糖刺激的胰岛素分泌(GSIS)是通过Ca2+依赖性机制发生的，该机制将细胞的去极化与来自电压门控Ca2+通道的细胞膜Ca2+流入和胰岛素颗粒的外分泌结合起来 [4] 。CDK5可能通过丝氨酸磷酸化使L型电压依赖性钙通道磷酸化，磷酸化后的钙(Ca2+)通道抑制Ca2+内流，减少胰岛素分泌；b) CDK5与p35 (CDK5的激活剂)结合 在高血糖条件下，诱导表达的calpain (一种钙依赖蛋白)切割P35蛋白产生活性P25，活性P25再与cdk5结合，形成cdk5-P25活性复合物 [5] ，活跃的cdk5进而使PDX1蛋白(一种胰岛素基因的转录因子)从细胞核转位到胞浆，由于胰岛素分泌被破坏，将会导致一系列与高血糖症有关的并发症 [6] 。如果采用基因干扰技术，敲除p35，可促进葡萄糖刺激并诱导胰岛素分泌，因此，Cdkal1表达的蛋白质耗竭或表达减少导致CDK5抑制作用减弱，胰岛素的分泌因此而减少 [7] 。2) K+-ATP途径 在高葡萄糖浓度的刺激下Cdkal1表达会减少ATP产生，使得葡萄糖诱导的K+-ATP通道应答反应减弱，随后Ca2+通道活性受损，通过减缓K+-ATP通道的K+输出和降低Ca2+通道的活性以此调控第一时相胰岛素分泌，由此可能引发T2DM [8] 。3) 甲硫转移酶途径 Cdkal1是哺乳动物内质网上膜结合蛋白，属于甲硫基转移酶家族，可催化N6-苏氨酰基–氨基甲酰腺苷(N6-threonyl-carbamoyl-adenosine, t6A)的2-甲硫基(2-methylthio, ms2)修饰，进而合成tRNALys (UUU)的2-甲硫基-N6-苏氨酰基–氨基甲酰腺苷37 (ms2t6A37)，这个修饰是AAA和AAG密码子精确转运所必须的。这种甲硫化修饰有效保证了胰岛素mRNA的准确翻译 [9] [10] [11] 。Dos等人通过LCMS质谱仪验证发现了Irp2 (铁调节蛋白2)缺陷引起的Cdkal1功能降低，减少了tRNALysUUU中的ms2t6A修饰，导致原胰岛素中赖氨酸密码子的误读，从而损害了胰岛素原的加工。由于胰岛素原的折叠或分裂不当，导致胰岛素原合成减少 [12] 。另有研究发现Cdkal1基因敲除小鼠中，胰岛β细胞线粒体存在ATP生成障碍和第一时相胰岛素分泌受损，提示Cdkal1亦可通过非CDK5依赖途径调节β细胞内胰岛素的释放，因而其基因突变也可导致罹患T2DM的风险增加 [8] 。

3. Cdkal1基因多态性与民族(种族)的关系

Setiawan提出，全世界各地不同民族或种族间糖尿病患病率显著不同 [13] 。个体/群体遗传结构的变化和环境危险因素的强度可能导致了该疾病的地理患病率和种族易感性的变化 [14] 。在2013年进行的一项横断面多民族调查中，比较了不同民族糖尿病的患病率，汉族等多数民族糖尿病粗患病率为14.7%，高于藏族、壮族、维吾尔族、回族等多数少数民族。藏族和回族糖尿病患病率显著低于汉族(P < 0.001) [15] 。全基因组关联研究(GWAS)则有助于识别与糖尿病风险增加相关的常见遗传变异 [16] 。到2018年，全基因组关联研究(GWAS)和GWAS荟萃分析已经确定了大约140个与T2DM相关的单核苷酸多态性(SNPs) [17] 。2020年有相关文献表明已经在欧洲人群明确超过450个二型糖尿病(T2D)的单核苷酸多态性(SNPs) [18] 。在欧洲血统的人群中通过GWAS鉴定的T2DM易感位点的SNPs在亚洲人群中亦显示出类似的效果 [19] 。迄今为止，Cdkal1基因的5个不同风险SNP位点已被鉴定，且均来自该基因内含子5：rs4712523 [20] 、rs6931514 [21] 、rs7756992 [22] 、rs10946398 [23] 和rs9465871 [24] ，这种与2型糖尿病相关的SNPs导致糖尿病发病风险增加约2倍 [25] 。国内外学者研究了不同地区、不同种族Cdkal1基因多态性与2型糖尿病的关系，发现其存在疾病易感性的问题。该基因在不同种族和人群中得到反复验证，是公认的易感基因之一 [26] 。早在2008年，中国人群T2DM与Cdkal1多态性的关系就已经得到证实。此外，也有研究人员指出该基因多态性与中国人群消瘦型T2DM的关联显著 [27] 。Cdkal1与不同人群T2DM的易感程度不一致，其中延安汉族 [28] 、浙江省温州地区汉族人群 [29] 等Cdkal1 rs7756992位点与2型糖尿病的关联。Cdkal1基因rs10946398、rs35612982、rs9465871的等位基因的突变在蒙古族人群中为风险突变，可能增加了T2DM的患病风险 [30] 。新疆地区研究则未发现Cdkal1的基因多态性可能与维吾尔族T2DM的发病风险有关联 [31] 。在韩国人群中，rs7756992和rs9465871与女性T2DM的易感性相关，而与男性无关 [32] 。此外，在荟萃分析中 [33] ，Cdkal1位点(rs7754840)发现高加索人和亚洲人之间存在显著异质性，该分析结合了先前欧洲白人、日本人、韩国人、中国香港人，而亚洲人中未观察到显著的异质性。在2013年花巍 [34] 等人进行的一项有关Cdkal1 rs7756992易感基因位点的Meta分析中，该位点G等位基因及GG基因型与欧洲人群T2DM发病有关，结果同样证实G等位基因及GG基因型与亚洲人T2DM发病密切相关。这些观察结果表明，这些Cdkal1变异体可能在中国人的糖尿病易感性中发挥更重要的作用。综上所述，Cdkal1基因在T2DM发生发展中具有重要作用，尽管这些结果仍存在争议需要在更广泛的人群中加以验证。

4. 结论

中国是一个多民族国家，因为各民族的生存环境的差别，不同民族的人在生活习性和饮食习惯上或多或少存在差别，糖尿病等慢性病的高发病率可归因于个人生活方式的不同，如：独特的饮食、生活习惯等。T2DM的发病机制目前还不是非常明确，随着遗传学和分子生物学及基因芯片技术的迅猛发展，T2DM人群易感基因问题越来越引起学者的重视。从民族(种族)不同遗传背景的角度，以不同民族、种族为研究对象，研究Cdkal1基因位点与T2DM的关联性，以期寻找到糖尿病患者人群中Cdkal1基因多态性与其它地区民族(种族)的共同点和独特性。为进一步开展糖尿病患者易感性基因位点的深入研究及发生机制研究奠定基础。大多数确定的易感性风险位点在东亚人和有欧洲血统的人群中是共有的，鉴于全球范围内T2DM遗传关联研究结果的不一致性，与T2DM相关的单核苷酸多态性中，大多数尚未进行与胰岛素相关性状的检查。若该位点作为一种新的治疗药物靶点，单个遗传标记的功能是有限的，应建立并结合多个位点联合效应的通用遗传模型来预测抗糖尿病药物的疗效。

文章引用

毛新玲,马生花. Cdkal1基因多态性与2型糖尿病易感性研究相关进展
Advances in the Study of Cdkal1 Gene Polymorphisms Related to Susceptibility to Type 2 Diabetes[J]. 临床医学进展, 2023, 13(06): 9363-9367. https://doi.org/10.12677/ACM.2023.1361310

参考文献

  1. 1. Wei, F.Y., Suzuki, T., Watanabe, S., et al. (2012) Deficit of tRNALys Modification by Cdkal1 Causes the Development of Type 2 Diabetes in Mice. Journal of Clinical Investigation, 121, 3598-3608. https://doi.org/10.1172/JCI58056

  2. 2. Cho, N.H., Shaw, J.E., Karuranga, S., Huang, Y., da Rocha Fernandes, J.D., Ohlrogge, A.W. and Malanda, B. (2018) IDF Diabetes Atlas: Global Estimates of Diabetes Prevalence for 2017 and Projections for 2045. Diabetes Research and Clinical Practice, 138, 271-281. https://doi.org/10.1016/j.diabres.2018.02.023

  3. 3. Scott, L.J., Mohlke, K.L., Bonnycastle, L.L., et al. (2007) A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants. Science, 316, 1341-1345. https://doi.org/10.1126/science.1142382

  4. 4. Kono, T., Ahn, G., Moss, D.R., et al. (2012) PPAR-γ Activation Restores Pancreatic Islet SERCA2 Levels and Prevents β-Cell Dysfunction under Conditions of Hyperglyce-mic and Cytokine Stress. Molecular Endocrinology, 26, 257-271. https://doi.org/10.1210/me.2011-1181

  5. 5. Ong, S.B., Lee, W.H., Shao, N.Y., et al. (2019) Stem Cell Reports Article Calpain Inhibition Restores Autophagy and Pre-vents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy. Stem Cell Reports, 12, 597-610. https://doi.org/10.1016/j.stemcr.2019.01.017

  6. 6. Ahmed, D. and Sharma, M. (2011) Cyclin-Dependent Kinase 5/p35/p39: A Novel and Imminent Therapeutic Target for Diabetes Mellitus. International Journal of Endocrinology, 2011, Article ID: 530274. https://doi.org/10.1155/2011/530274

  7. 7. Yin, X., Warner, D.R., Roberts, E.A., et a1. (2005) Novel Interaction between Nuclear Co-Activator CBP and the CDK5 Activator Binding Protein—C53. International Journal of Molecular Medicine, 16, 251-256. https://doi.org/10.3892/ijmm.16.2.251

  8. 8. Ohara-Imaizumi, M., Yoshida, M., Aoyagi, K., et al. (2010) Deletion of CDKAL1 Affects Mitochondrial ATP Generation and First-Phase Insulin Exocytosis. PLOS ONE, 5, e15553. https://doi.org/10.1371/journal.pone.0015553

  9. 9. Brambillasca, S., Altkrueger, A., Colombo, S.F., et a1. (2012) CDK5 Regulatory Subunit-Associated Protein 1-Like 1 (CDKALl) Is a Tail-Anchored Protein in the Endoplasmic Retic-ulum (ER) of Insulinoma Cells. Journal of Biological Chemistry, 287, 41808-41819. https://doi.org/10.1074/jbc.M112.376558

  10. 10. Torkko, J.M., Primo, M.E., Dirkx, R., et a1. (2015) Stability of proICA512/IA-2 and Its Targeting to Insulin Secretory Granules Require β4-Sheet-Mediated Dimerization of Its Ecto-domain in the Endoplasmic Reticulum. Molecular and Cellular Biology, 35, 914-927. https://doi.org/10.1128/MCB.00994-14

  11. 11. Wei, F.Y. and Tomizawa, K. (2012) Development of Type 2 Diabetes Caused by a Deficiency of a tRNA1ys Modification. Islets, 4, 71-73. https://doi.org/10.4161/isl.18262

  12. 12. Dos, S., Maria, C.F., Cole, P.A., Susanne, N., Kimberly, B.Z., Steven, J.R., et al. (2020) Irp2 Regulates Insulin Production through Iron-Mediated Cdkal1-Catalyzed tRNA Modification. Nature Communications, 11, Article No. 296. https://doi.org/10.1038/s41467-019-14004-5

  13. 13. Setiawan, V.W., Hernandez, B.Y., Lu, S.C., et al. (2014) Diabe-tes and Racial/Ethnic Differences in Hepatocellular Carcinoma Risk: The Multiethnic Cohort. Journal of the National Cancer Institute, 106, dju326. https://doi.org/10.1093/jnci/dju326

  14. 14. Reddy, B.M., Pranavchand, R. and Latheef, S.A.A. (2019) Overview of Genomics and Post-Genomics Research on Type 2 Diabetes Mellitus: Future Perspectives and a Framework for Further Studies. Journal of Biosciences, 44, Article Number: 21. https://doi.org/10.1007/s12038-018-9818-6

  15. 15. Wang, L.M., Gao, P., Zhang, M., et al. (2017) Prevalence and Ethnic Pattern of Diabetes and Prediabetes in China in 2013. JAMA: The Journal of the American Medical Association, 317, 2515-2523. https://doi.org/10.1001/jama.2017.7596

  16. 16. Bartolomé, A. (2022) Stem Cell-Derived β Cells: A Versatile Re-search Platform to Interrogate the Genetic Basis of β Cell Dysfunction. International Journal of Molecular Sciences, 23, Article 501. https://doi.org/10.3390/ijms23010501

  17. 17. Morris, A.P. (2018) Progress in Defining the Genetic Con-tribution to Type 2 Diabetes Susceptibility. Current Opinion in Genetics & Development, 50, 41-51. https://doi.org/10.1016/j.gde.2018.02.003

  18. 18. Goodarzi, M.O., Palmer, N.D., Cui, J.R., et al. (2020) Classification of Type 2 Diabetes Genetic Variants and a Novel Genetic Risk Score Association With Insulin Clearance. The Journal of Clinical Endocrinology and Metabolism, 105, 1251-1260. https://doi.org/10.1210/clinem/dgz198

  19. 19. Tan, J.T., Ng, D.P.K., Siti, N., et al. (2010) Polymorphisms Identified through Genome-Wide Association Studies and Their Associa-tions with Type 2 Diabetes in Chinese, Malays, and Asian-Indians in Singapore. The Journal of Clinical Endocrinology & Metabolism, 95, 390-397. https://doi.org/10.1210/jc.2009-0688

  20. 20. Rung, J., Cauchi, S., Albrechtsen, A., Shen, L., Rocheleau, G., Cavalcanti-Proença, C., et al. (2009) Genetic Variant near IRS1 Is Associated with Type 2 Diabetes, Insulin Resistance and Hyperinsulinemia. Nature Genetics, 41, 1110-1115. https://doi.org/10.1038/ng.443

  21. 21. Zeggini, E., Scott, L.J., Saxena, R., Voight, B.F., Marchini, J.L., Hu, T., et al. (2008) Meta-Analysis of Genome-Wide Association Data and Largescale Replication Identifies Additional Susceptibility Loci for Type 2 Diabetes. Nature Genetics, 40, 638-645. https://doi.org/10.1038/ng.120

  22. 22. Lasram, K., Ben Halim, N., Benrahma, H., Mediene Benchekor, S., Arfa, I., Hsouna, S., et al. (2015) Contribution of CDKAL1 rs7756992 and IGF2BP2 rs4402960 Polymorphisms in Type 2 Diabetes, Diabetic Complications, Obesity Risk and Hy-pertension in the Tunisian Population. Journal of Diabetes, 7, 102-113. https://doi.org/10.1111/1753-0407.12147

  23. 23. Saxena, R., Voight, B.F., Lyssenko, V., Burtt, N.P., de Bakker, P.I., Chen, H., et al. (2007) Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels. Science, 316, 1331-1336. https://doi.org/10.1126/science.1142358

  24. 24. The Wellcome Trust Case Control Consortium (2007) Genome-Wide Association Study of 14,000 Cases of Seven Common Diseases and 3,000 Shared Controls. Nature, 447, 661-678. https://doi.org/10.1038/nature05911

  25. 25. Zhou, B., Wei, F.Y., Kanai, N., Fujimura, A., Kaitsuka, T. and Tomizawa, K. (2014) Identification of a Splicing Variant That Regulates Type 2 Diabetes Risk Factor CDKAL1 Level by a Cod-ing-Independent Mechanism in Human. Human Molecular Genetics, 23, 4639-4650. https://doi.org/10.1093/hmg/ddu184

  26. 26. Wei, F.Y. and Tomizawa, K. (2011) Functional Loss of Cdkal1, a Novel tRNA Modification Enzyme, Causes the Development of Type 2 Diabetes. Endocrine Journal, 58, 819-825. https://doi.org/10.1507/endocrj.EJ11-0099

  27. 27. Kong, X.M., Xing, X.Y., et al. (2016) Genetic Variants Associated with Lean and Obese Type 2 Diabetes in a Han Chinese Population: A Case—Control Study. Medicine, 95, e3841. https://doi.org/10.1097/MD.0000000000003841

  28. 28. 杜伟平. 延安汉族人群2型糖尿病易感基因的多态性研究[D]: [硕士学位论文]. 延安: 延安大学, 2019.

  29. 29. 李伟, 牛庆, 李霞莲, 沈飞霞, 施红英, 曹淑彦, 张婷, 李春梅, 吕建新. CDKAL1基因rs7756992位点多态性与2型糖尿病发病风险及临床特征关联分析[J]. 温州医学院学报, 2013, 43(3): 141-146. https://doi.org/10.13771/j.cnki.33-1386/r.2013.03.012

  30. 30. 陈乐. 蒙古族2型糖尿病与CDKAL1基因、KCNQ1基因多态性及基因-基因、基因-环境交互作用研究[D]: [硕士学位论文]. 呼和浩特: 内蒙古医科大学, 2021. https://doi.org/10.27231/d.cnki.gnmyc.2021.000001

  31. 31. 肖珊. 维吾尔族2型糖尿病相关基因的多态性及基因-基因、基因-环境交互作用研究[D]: [博士学位论文]. 乌鲁木齐: 新疆医科大学, 2015. https://doi.org/10.7666/d.D800880

  32. 32. Ryoo, H., Woo, J., Kim, Y. and Lee, C. (2011) Heterogeneity of Genetic Associations of CDKAL1 and HHEX with Susceptibility of Type 2 Diabetes Mellitus by Gender. European Journal of Human Genetics, 19, 672-675. https://doi.org/10.1038/ejhg.2011.6

  33. 33. Wu, Y., Li, H., Loos, R.J.F., et al. (2008) Common Variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE Genes Are Associated with Type 2 Diabetes and Impaired Fasting Glucose in a Chinese Han Population. Diabetes, 57, 2834-2842. https://doi.org/10.2337/db08-0047

  34. 34. 花巍, 尹立群, 步怀恩, 等. CDKAL1基因rs7756992位点多态性与2型糖尿病关系的Meta分析[J]. 天津医药, 2013, 41(3): 244-251. https://doi.org/10.3969/j.issn.0253-9896.2013.03.015

    35. NOTES

    *通讯作者。

期刊菜单