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Protective effect of the rare variant rs13266634C/T of the SLC30A8 gene in the genetic background of the development of type 2 diabetes in Turkish population

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Abstract

Background

The SLC30A8 gene encodes zinc transporter-8 (ZnT8), highly expressed in insulin-secreting pancreatic beta cells, and may contribute to insulin processing and secretion. The SNP 13266634C/T (R325W change) in the SLC30A8 gene has been associated with type 2 diabetes (T2D) development. Genome-wide association studies and subsequent population studies including Europeans and Asians have demonstrated that the rare allele T (Trp325) of SNP 13266634 in the SLC30A8 gene is protective against T2D.

Aim

We aimed to investigate whether the SNP rs13266634C/T is associated with T2D and its phenotypes in Turkey, which geographically connects Asia and Europe.

Materials and methods

In our study, 650 nonobese individuals (366 T2D and 284 healthy individuals) were enrolled. Target SNP was genotyped by real-time PCR using the LightSNiP Genotyping Assay System.

Results

The frequency of the T allele was lower in the T2D group than in the healthy control group (14.6% vs. 24.5%, respectively). The rare variant T of SNP rs13266634 in SLC30A8, located in the last exon of the gene, is associated with an increased c-peptide level, and it was 47.2% protective against type 2 diabetes compared to the C allele (OR = 0.528, 95% CI: 0.399–0.699, p < .001).

Conclusions

Our findings indicate consistently with other studies that a rare variant of rs13266634C/T is protective against T2D, as the related first report in the nonobese Turkish population. Comprehensive studies to better understand the envisaged vital molecular role of SLC30A8 in pancreatic beta cells may contribute to developing therapeutic approaches.

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Data Availability

All data generated or analysed during this study are included in this published article.

Change history

References

  1. Prasad AS. Zinc: an overview. Nutrition. 1995;11(1 Suppl):93–9.

    CAS  PubMed  Google Scholar 

  2. Maret W, Sandstead HH. Zinc requirements and the risks and benefits of zinc supplementation. J Trace Elem Med Biol. 2006;20(1):3–18.

    Article  CAS  PubMed  Google Scholar 

  3. Hennigar SR, Kelleher SL. Zinc networks: the cell-specifi compartmentalization of zinc for specialized functions. Biol Chem. 2012;393:565–78.

    Article  CAS  PubMed  Google Scholar 

  4. Maret W. Zinc biochemistry: from a single zinc enzyme to a key element of life. Adv Nutr. 2013;4:82–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kambe T. Molecular architecture and function of ZnT transporters. Curr Top Membr. 2012;69:199–220.

    Article  CAS  PubMed  Google Scholar 

  6. Andreini C, Banci L, Bertini I, Rosato A. Counting the zinc-proteins encoded in the human genome. J Proteome Res. 2006;5:196–201.

    Article  CAS  PubMed  Google Scholar 

  7. Chimienti F, Favier A, Seve M. ZnT-8, a pancreatic beta-cell-specific zinc transporter. Biometals. 2005;18(4):313–7.

    Article  CAS  PubMed  Google Scholar 

  8. Vinkenborg JL, Nicolson TJ, Bellomo EA, Koay MS, Rutter GA, Merkx M. Genetically encoded FRET sensors to monitor intracellular Zn2+ homeostasis. Nat Methods. 2009;6:737–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gerber PA, Bellomo EA, Hodson DJ, Meur G, Solomou A, Mitchell RK, Hollinshead M, et al. Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells. Diabetologia. 2014;57:1635–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rutter GA, Chimienti F. SLC30A8 mutations in type 2 diabetes. Diabetologia. 2015;58:31–6.

    Article  CAS  PubMed  Google Scholar 

  11. Chimienti F, Devergnas S, Favier A, Seve M. Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes. 2004;53:2330–7.

    Article  CAS  PubMed  Google Scholar 

  12. Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007;22;445(7130):881–5.

    Article  Google Scholar 

  13. Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, et al. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661–78.

    Article  CAS  Google Scholar 

  14. Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007;316(5829):1341–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet. 2010;42(7):579–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Morris AP, Voight BF, Teslovich TM, Ferreira T, Segrè AV, Steinthorsdottir V, Strawbridge RJ, et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012;44:981–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cheng L, Zhang D, Zhou L, Zhao J, Chen B. Association between SLC30A8 rs13266634 polymorphism and type 2 diabetes risk: a meta-analysis. Med Sci Monit. 2015;21:2178–89.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Boesgaard TW, Zilinskaite J, Vanttinen M, Laakso M, Jansson PA, Hammarstedt A, Smith U, et al. The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients–the EUGENE2 study. Diabetologia. 2008;51(5):816–20.

    Article  CAS  PubMed  Google Scholar 

  19. Saxena R, Elbers CC, Guo Y, Peter I, Gaunt TR, Mega JL, Lanktree MB, et al. Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci. Am J Hum Genet. 2012;90(3):410-25.22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee YH, Kang ES, Kim SH, Han SJ, Kim CH, Kim HJ, Ahn CW, et al. Association between polymorphisms in SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1, KCNQ1 and type 2 diabetes in the Korean population. J Hum Genet. 2008;53(11–12):991-8. 20.

    Article  CAS  PubMed  Google Scholar 

  21. Ng MC, Park KS, Oh B, Tam CH, Cho YM, Shin HD, Lam VK, et al. Implication of genetic variants near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in type 2 diabetes and obesity in 6,719 Asians. Diabetes. 2008;57(8):2226–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Omori S, Tanaka Y, Takahashi A, Hirose H, Kashiwagi A, Kaku K, Kawamori R, Nakamura Y, Maeda S. Association of CDKAL1, IGF2BP2, CDKN2A/B, HHEX, SLC30A8, and KCNJ11 with susceptibility to type 2 diabetes in a Japanese population. Diabetes. 2008;57(3):791–5.

    Article  CAS  PubMed  Google Scholar 

  23. Mashal S, Khanfar M, Al-Khalayfa S, Srour L, Mustafa L, Hakooz NM, Zayed AA, Khader YS, Azab B. SLC30A8 gene polymorphism rs13266634 associated with increased risk for developing type 2 diabetes mellitus in Jordanian population. Gene. 2021;5(768): 145279.

    Article  Google Scholar 

  24. Arikoglu H, Erkoc-Kaya D, Ipekci SH, Gokturk F, Iscioglu F, Korez MK, Baldane S, Gonen MS. Type 2 diabetes is associated with the MTNR1B gene, a genetic bridge between circadian rhythm and glucose metabolism, in a Turkish population. Mol Biol Rep. 2021;48(5):4181–9.

    Article  CAS  PubMed  Google Scholar 

  25. Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, Rewers M, Eisenbarth GS, Jensen J, Davidson HW, Hutton JC. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci USA. 2007;104:17040–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tamaki M, Fujitani Y, Hara A, Uchida T, Tamura Y, Takeno K, Kawaguchi M, et al. The diabetes susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J Clin Invest. 2013;23:4513–24.

    Article  Google Scholar 

  27. Gu HF. Genetic, Epigenetic and biological effects of zinc transporter (SLC30A8) in type 1 and type 2 diabetes. Curr Diabetes Rev. 2017;13(2):132–40.

    Article  CAS  PubMed  Google Scholar 

  28. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316(5829):1331–6.

    Article  CAS  PubMed  Google Scholar 

  29. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007;316(5829):1336–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yaghootkar H, Frayling TM. Recent progress in the use of genetics to understand links between type 2 diabetes and related metabolic traits. Genome Biol. 2013;14(3):203.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Salem SD, Saif-Ali R, Ismail IS, Al-Hamodi Z, Muniandy S. Contribution of SLC30A8 variants to the risk of type 2 diabetes in a multi-ethnic population: a case control study. BMC Endocr Disord. 2014;14(1):2.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Khan IA, Jahan P, Hasan Q, Rao P. Validation of the association of TCF7L2 and SLC30A8 gene polymorphisms with post-transplant diabetes mellitus in Asian Indian population. Intractable Rare Dis Res. 2015;4(2):87–92.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Li Y-Y, Lu X-Z, Wang H, Yang X-X, Geng H-Y, Gong G, Zhan Y-Y, Kim HJ, Yang Z-J. Solute carrier family 30 member 8 gene 807C/T polymorphism and type 2 diabetes mellitus in the Chinese population: a meta-analysis including 6,942 subjects. Front Endocrinol. 2018;9:263.

    Article  Google Scholar 

  34. Goyal Y, Verma AK, Kumar S, Bhatt D, Ahmad F, Dev K. Association of SLC30A8 (rs13266634) and GLIS3 (rs7034200) gene variant in development of type 2 diabetes mellitus in Indian population: a case-control study. Gene Reports. 2022;28: 101655.

    Article  CAS  Google Scholar 

  35. Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, Mahajan A, et al. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet. 2014;46:357–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Flannick J, Mercader JM, Fuchsberger C, Udler MS, Mahajan A, Wessel J, Teslovich TM, et al. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature. 2019;570:71–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Parsons DS, Hogstrand C, Maret W. The C-terminal cytosolic domain of the human zinc transporter ZnT8 and its diabetes risk variant. FEBS J. 2018;285:1237–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dwivedi OP, Lehtovirta M, Hastoy B, Chandra V, Krentz NAJ, Kleiner S, Jain D, et al. Loss of ZnT8 function protects against diabetes by enhanced insulin secretion. Nat Genet. 2019;51:1596–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kirchhof K, Machicao F, Haupt A, Schäfer SA, Tschritter O, Staiger H, Stefan N, Häring HU, Fritsche A. Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia. 2008;51:597–601.

    Article  Google Scholar 

  40. Majithia AR, Jablonski KA, McAteer JB, Mather KJ, Goldberg RB, Kahn SE, Florez JC, DPP Research Group. Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and afer lifestyle, metformin or troglitazone intervention in the diabetes prevention program. Diabetologia. 2011;54:2570–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gorus FK, Balti EV, Vermeulen I, Demeester S, Van Dalem A, Costa O, Dorchy H, Tenoutasse S, Mouraux T, De Block C, Gillard P, Decochez K, Wenzlau JM, Hutton JC, Pipeleers DG, Weets I, Belgian Diabetes Registry. Screening for insulinoma antigen 2 and zinc transporter 8 autoantibodies: a cost-effective and age-independent strategy to identify rapid progressors to clinical onset among relatives of type 1 diabetic patients. Clin Exp Immunol. 2013;171:82–90.

    Article  CAS  PubMed  Google Scholar 

  42. United States The Regents of the University of Colorado, a body corporate (Denver, CO, US). 2015. p. 9023984. https://www.freepatentsonline.com/9023984.html.

  43. Elmaoğulları S, Uçaktürk SA, Elbeg Ş, Döğer E, Tayfun M, Gürbüz F, Bideci A. Prevalence of ZnT8 antibody in Turkish children and adolescents with new onset type 1 diabetes. J Clin Res Pediatr Endocrinol. 2018;10(2):108–12.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Andersson C, Larsson K, Vaziri-Sani F, Lynch K, Carlsson A, Cedervall E, Jönsson B, Neiderud J, Månsson M, Nilsson A, Lernmark A, Elding Larsson H, Ivarsson SA. The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes. Autoimmunity. 2011;44:394–405.

    Article  CAS  PubMed  Google Scholar 

  45. Vaziri-Sani F, Oak S, Radtke J, Lernmark K, Lynch K, Agardh CD, Cilio CM, Lethagen AL, Ortqvist E, Landin-Olsson M, Törn C, Hampe CS. ZnT8 autoantibody titers in type 1 diabetes patients decline rapidly after clinical onset. Autoimmunity. 2010;43:598–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yang L, Luo S, Huang G, Peng J, Li X, Yan X, Lin J, Wenzlau JM, Davidson HW, Hutton JC, Zhou Z. The diagnostic value of zinc transporter 8 autoantibody (ZnT8A) for type 1 diabetes in Chinese. Diabetes Metab Res Rev. 2010;26:579–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. WHO. 2022. https://www.who.int/health-topics/diabetes. Accessed 21 Dec 2021.

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Acknowledgments

This work was supported by the Scientific and Technological Research Council of Turkey (213S035).

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Authors and Affiliations

  1. Department of Medical Biology, Faculty of Medicine, Selcuk University, Konya, Turkey

    Dudu Erkoc-Kaya & Hilal Arikoglu

  2. Department of Biostatistics, Faculty of Medicine, Selcuk University, Konya, Turkey

    Kazim Muslu Korez

  3. Department of Endocrinology and Metabolic Diseases, Hisar Hospital Intercontinental, Istanbul, Turkey

    Suleyman Hilmi Ipekci

  4. Department of Endocrinology and Metabolic Diseases, Faculty of Medicine, Selcuk University, Konya, Turkey

    Suleyman Baldane

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  1. Dudu Erkoc-Kaya
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  2. Hilal Arikoglu
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  3. Kazim Muslu Korez
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  4. Suleyman Hilmi Ipekci
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  5. Suleyman Baldane
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Contributions

Hilal Arikoglu: concept, study design, analysis, interpretation, writing the manuscript. Dudu Erkoc-Kaya: literature search, SNP analysis, interpretation, critical review. Kazim Muslu Korez: statistical analysis, interpretation. Suleyman Hilmi Ipekci: management of patients. Suleyman Baldane: collecting patient data.

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Correspondence to Hilal Arikoglu.

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Research involving human participants and/or animals

The study was approved by the Selcuk University Faculty of Medicine Ethics Committee (2013/305). The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

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Erkoc-Kaya, D., Arikoglu, H., Korez, K.M. et al. Protective effect of the rare variant rs13266634C/T of the SLC30A8 gene in the genetic background of the development of type 2 diabetes in Turkish population. Int J Diabetes Dev Ctries 43, 1052–1060 (2023). https://doi.org/10.1007/s13410-023-01195-3

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