SpringerLink
Log in

The common rs13266634 C > T variant in SLC30A8 contributes to the heterogeneity of phenotype and clinical features of both type 1 and type 2 diabetic subtypes

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

Aims

T2D and T1D are phenotypically heterogeneous. This study aims to reveal the relationship between the common SLC30A8 rs13266634 variant and subgroups of T2D and T1D and their clinical characteristics.

Methods

We included 3158 OGTT-based healthy controls, unrelated 1754 T2D, and 1675 autoantibody-positive T1D individuals. The associations between rs13266634 and subtypes of T2D, T1D, autoantibody status and glycemic-related quantitative traits were performed by binary logistic regression analysis under the additive model and multiple linear regression with appropriate adjustment.

Results

We found that the T allele of rs13266634 was protectively associated with lean (OR = 0.810, P = 6.91E–04) but not obese T2D with considerable heterogeneity (P = 0.018). This allele also conferred significant protection with T1D of single (OR = 0.847, P = 9.76E–03), but not multi autoantibodies with substantial heterogeneity (P = 0.005). This variant significantly affected OGTT-related insulin release in lean (P = 2.66E–03, 3.88E–03 for CIR and DI, respectively) but not obese healthy individuals. Furthermore, rs13266634 T allele correlated with the risk of ZnT8A (OR = 1.440, P = 3.31E–05) and IA-2A (OR = 1.219, P = 1.32E–03) positivity, with more effect size in children/adolescents compared with adult-onset T1D subtypes.

Conclusions

These suggested that the SLC30A8 rs13266634 variant might be put into genetic risk scores to assess the risk of the subtypes of T1D and T2D and their related clinical features.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Chimienti F, Devergnas S, Favier A, Seve M (2004) Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes 53:2330–2337

    Article  CAS  Google Scholar 

  2. Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885

    Article  CAS  Google Scholar 

  3. Spracklen CN, Horikoshi M, Kim YJ et al (2020) Identification of type 2 diabetes loci in 433,540 East Asian individuals. Nature 582:240–245

    Article  CAS  Google Scholar 

  4. Vujkovic M, Keaton JM, Lynch JA et al (2020) Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis. Nat Genet 52:680–691

    Article  CAS  Google Scholar 

  5. Stancáková A, Kuulasmaa T, Paananen J et al (2009) Association of 18 confirmed susceptibility loci for type 2 diabetes with indices of insulin release, proinsulin conversion, and insulin sensitivity in 5,327 nondiabetic Finnish men. Diabetes 58:2129–2136

    Article  Google Scholar 

  6. ’t Hart LM, Simonis-Bik AM, Nijpels G et al (2010) Combined risk allele score of eight type 2 diabetes genes is associated with reduced first-phase glucose-stimulated insulin secretion during hyperglycemic clamps. Diabetes 59:287–292

    Article  CAS  Google Scholar 

  7. Walford GA, Green T, Neale B et al (2012) Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism. Diabetologia 55:331–339

    Article  CAS  Google Scholar 

  8. **ang J, Li XY, Xu M et al (2008) Zinc transporter-8 gene (SLC30A8) is associated with type 2 diabetes in Chinese. J Clin Endocrinol Metab 93:4107–4112

    Article  CAS  Google Scholar 

  9. Haupt A, Guthoff M, Schäfer SA et al (2009) The inhibitory effect of recent type 2 diabetes risk loci on insulin secretion is modulated by insulin sensitivity. J Clin Endocrinol Metab 94(5):1775–1780

    Article  CAS  Google Scholar 

  10. Qu HQ, Grant SF, Bradfield JP et al (2008) Association analysis of type 2 diabetes Loci in type 1 diabetes. Diabetes 57:1983–1986

    Article  CAS  Google Scholar 

  11. Raj SM, Howson JM, Walker NM et al (2009) No association of multiple type 2 diabetes loci with type 1 diabetes. Diabetologia 52:2109–2116

    Article  CAS  Google Scholar 

  12. Xu K, Zha M, Wu X et al (2011) Association between rs13266634 C/T polymorphisms of solute carrier family 30 member 8 (SLC30A8) and type 2 diabetes, impaired glucose tolerance, type 1 diabetes–a meta-analysis. Diabetes Res Clin Pract 91:195–202

    Article  CAS  Google Scholar 

  13. Howson JM, Krause S, Stevens H et al (2012) Genetic association of zinc transporter 8 (ZnT8) autoantibodies in type 1 diabetes cases. Diabetologia 55:1978–1984

    Article  CAS  Google Scholar 

  14. Zhu M, Xu K, Chen Y et al (2019) Identification of Novel T1D Risk Loci and Their Association With Age and Islet Function at Diagnosis in Autoantibody-Positive T1D Individuals: Based on a Two-Stage Genome-Wide Association Study. Diabetes Care 42:1414–1421

    Article  CAS  Google Scholar 

  15. Perry JR, Voight BF, Yengo L et al (2012) Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases. PLoS Genet 8:e1002741

    Article  CAS  Google Scholar 

  16. Liley J, Todd JA, Wallace C (2017) A method for identifying genetic heterogeneity within phenotypically defined disease subgroups. Nat Genet 49:310–316

    Article  CAS  Google Scholar 

  17. Ning G; Reaction Study Group (2012) Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study. J Diabetes 4:172–173

    Article  Google Scholar 

  18. Adler A, Bennett P, Colagiuri Chair S, et al (2021) Reprint of: classification of diabetes mellitus. Diabetes Res Clin Pract. 108972.

  19. Gu Y, **ao L, Gu W et al (2018) Rs2227982 and rs2227981 in PDCD1 gene are functional SNPs associated with T1D risk in East Asian. Acta Diabetol 55(8):813–819

    Article  CAS  Google Scholar 

  20. Pan XF, Wang L, Pan A (2021) Epidemiology and determinants of obesity in China. Lancet Diabetes Endocrinol 9(6):373–392

    Article  Google Scholar 

  21. Cauchi S, Nead KT, Choquet H et al (2008) The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies. BMC Med Genet 9:45

    Article  Google Scholar 

  22. Timpson NJ, Lindgren CM, Weedon MN et al (2009) Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. Diabetes 58:505–510

    Article  CAS  Google Scholar 

  23. Dwivedi OP, Lehtovirta M, Hastoy B et al (2019) Loss of ZnT8 function protects against diabetes by enhanced insulin secretion. Nat Genet 51:1596–1606

    Article  CAS  Google Scholar 

  24. Kirchhoff K, Machicao F, Haupt A et al (2008) Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia 51:597–601

    Article  CAS  Google Scholar 

  25. Iwata M, Maeda S, Kamura Y et al (2012) Genetic risk score constructed using 14 susceptibility alleles for type 2 diabetes is associated with the early onset of diabetes and may predict the future requirement of insulin injections among Japanese individuals. Diabetes Care 35:1763–1770

    Article  CAS  Google Scholar 

  26. Choi CHJ, Cohen P (2017) How does obesity lead to insulin resistance? Elife 6:e33298

    Article  Google Scholar 

  27. Andersen ML, Vaziri-Sani F, Delli A et al (2012) Association between autoantibodies to the Arginine variant of the Zinc transporter 8 (ZnT8) and stimulated C-peptide levels in Danish children and adolescents with newly diagnosed type 1 diabetes. Pediatr Diabetes 13:454–462

    Article  CAS  Google Scholar 

  28. Nielsen LB, Vaziri-Sani F, Pörksen S et al (2011) Relationship between ZnT8Ab, the SLC30A8 gene and disease progression in children with newly diagnosed type 1 diabetes. Autoimmunity 44:616–623

    Article  CAS  Google Scholar 

  29. Aylward A, Chiou J, Okino ML et al (2018) (2018) Shared genetic risk contributes to type 1 and type 2 diabetes etiology. Hum Mol Genet. https://doi.org/10.1093/hmg/ddy314

    Article  PubMed  Google Scholar 

  30. Redondo MJ, Geyer S, Steck AK et al (2018) TCF7L2 genetic variants contribute to phenotypic heterogeneity of type 1 diabetes. Diabetes Care 41:311–317

    Article  CAS  Google Scholar 

  31. Syring KE, Bosma KJ, Goleva SB et al (2020) Potential positive and negative consequences of ZnT8 inhibition. J Endocrinol 246:189–205

    Article  CAS  Google Scholar 

  32. Cerolsaletti K, Hao W, Greenbaum CJ (2019) Genetics Coming of Age in Type 1 Diabetes. Diabetes Care 42:189–191

    Article  CAS  Google Scholar 

  33. Wenzlau JM, Liu Y, Yu L et al (2008) A common nonsynonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes. Diabetes 57:2693–2697

    Article  CAS  Google Scholar 

  34. Long AE, George G, Williams CL (2021) Persistence of Islet Autoantibodies after diagnosis in Type 1 Diabetes. Diabet Med 6:e14712

    Google Scholar 

  35. Delli AJ, Vaziri-Sani F, Lindblad B et al (2012) Zinc transporter 8 autoantibodies and their association with SLC30A8 and HLA-DQ genes differ between immigrant and Swedish patients with newly diagnosed type 1 diabetes in the better diabetes diagnosis study. Diabetes 61:2556–2564

    Article  CAS  Google Scholar 

  36. Giacconi R, Malavolta M, Chiodi L et al (2018) ZnT8 Arg325Trp polymorphism influences zinc transporter expression and cytokine production in PBMCs from patients with diabetes. Diabetes Res Clin Pract 144:102–110

    Article  CAS  Google Scholar 

  37. Li L, Bai S, Sheline CT (2017) hZnT8 (Slc30a8) transgenic mice that overexpress the R325W polymorph have reduced Islet Zn2+ and proinsulin levels, increased glucose tolerance after a high-fat diet, and altered levels of pancreatic zinc binding proteins. Diabetes 66:551–559

    Article  CAS  Google Scholar 

  38. Merriman C, Huang Q, Rutter GA, Fu D (2016) Lipid-tuned zinc transport activity of human ZNT8 protein correlates with risk for type-2 diabetes. J Biol Chem 291:26950–26957

    Article  CAS  Google Scholar 

  39. Xu J, Wijesekara N, Regeenes R et al (2021) Pancreatic β cell-selective zinc transporter 8 insufficiency accelerates diabetes associated with islet amyloidosis. JCI Insight 6:143037

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (81670715 and 82070803), Jiangsu Province Youth Medical Talents Project (QNRC2016584), the Natural Science Foundation of Jiangsu Province (BK2012486), Jiangsu Government Scholarship for Overseas Studies (JS-2013-260), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Author information

Author notes

  1. Kuanfeng Xu, Hui Lv and Jie Zhang authors have contributed equally to work.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, First Affiliated Hospital of Nan**g Medical University, Nan**g, 210029, China

    Kuanfeng Xu, Hui Lv, Jie Zhang, Heng Chen, Yunqiang He, Min Shen, Yu Qian, Hemin Jiang, Hao Dai, Shuai Zheng, Tao Yang & Qi Fu

Authors
  1. Kuanfeng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Heng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yunqiang He
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Min Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hemin Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hao Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shuai Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Qi Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Kuanfeng Xu directed the study design, performed statistical analysis and interpretation of data, and drafted the initial manuscript. Hui Lv, Jie Zhang, and Yunqiang He were responsible for the analysis and interpretation of data. Hao Dai and Shuai Zheng contributed to the collection and selection of samples. Heng Chen, Min Shen, Yu Qian, Hemin Jiang contributed to Laboratory measurements. Qi Fu and Tao Yang gave a critical revision of the manuscript. All the co-authors gave the final approval of the version.

Corresponding authors

Correspondence to Kuanfeng Xu, Tao Yang or Qi Fu.

Ethics declarations

Conflict of interest

The authors declare that there is no duality of interest associated with this manuscript.

Human and Animal Rights

This study was a study with human samples, which was approved by the Ethics Committee from the First Affiliated Hospital of Nan**g Medical University and conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

We also stated that that all persons gave their informed consent prior to their inclusion in the study.

Additional information

Managed by Massimo Porta.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 411 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, K., Lv, H., Zhang, J. et al. The common rs13266634 C > T variant in SLC30A8 contributes to the heterogeneity of phenotype and clinical features of both type 1 and type 2 diabetic subtypes. Acta Diabetol 59, 545–552 (2022). https://doi.org/10.1007/s00592-021-01831-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-021-01831-6

Keywords

Search

Navigation