Skip to main content

Association analysis of HHEX gene variant with type 2 diabetes risk

Abstract

Background

Type 2 diabetes mellitus (T2DM) is a common, chronic, and complex disorder that is influenced by interactions between genetic and environmental factors. The hematopoietically expressed homeobox (HHEX) gene, which affects insulin sensitivity and secretion, is a candidate gene for the pathogenesis of T2DM.

Objective

The purpose of this study was to investigate the effect of the HHEX genetic variant, rs1111875, on the T2DM risk in a group of Iranian patients for the first time.

Methods

A total of 108 T2DM patients and 100 normal subjects were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

Results

There was significant difference in genotypes and alleles frequency of rs1111875 between both case and control groups (p < 0.001). The frequency of the G allele was significantly higher in cases (87.5%) compared with controls (27%) (OR = 18.92, CI = 11.06–32.69, p < 0.001).

Conclusion

Our findings suggest that the rs1111875 variant of the HHEX gene could be considered a strong risk factor for T2DM development.

This is a preview of subscription content, access via your institution.

Fig. 1

Data availability

Data from this project will be available to share.

References

  1. Kifagi C, Makni K, Boudawara M, Mnif F, Hamza N, Abid M, et al. Association of genetic variations in TCF7L2, SLC30A8, HHEX, LOC387761, and EXT2 with type 2 diabetes mellitus in Tunisia. Genet Test Mol Biomarkers. 2011;15(6):399–405.

    CAS  Article  Google Scholar 

  2. Shahbazian H, Aleali AM, Amani R, Namjooyan F, Cheraghian B, Latifi SM, et al. Effects of saffron on homocysteine, and antioxidant and inflammatory biomarkers levels in patients with type 2 diabetes mellitus: a randomized double-blind clinical trial. Avicenna J Phytomed. 2019;9(5):436–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Hindy G, Mollet IG, Rukh G, Ericson U, Orho-Melander M. Several type 2 diabetes-associated variants in genes annotated to WNT signaling interact with dietary fiber in relation to incidence of type 2 diabetes. Genes Nutr. 2016;11(1):6.

    Article  Google Scholar 

  4. Votsi C, Toufexis C, Michailidou K, Antoniades A, Skordis N, Karaolis M, et al. Type 2 diabetes susceptibility in the Greek-Cypriot population: replication of associations with TCF7L2, FTO, HHEX, SLC30A8 and IGF2BP2 polymorphisms. Genes. 2017;8(1):16.

    Article  Google Scholar 

  5. García-Chapa EG, Leal-Ugarte E, Peralta-Leal V, Durán-González J, Meza-Espinoza JP. Genetic epidemiology of type 2 diabetes in Mexican mestizos. Biomed Res Int. 2017;2017:1–10.

    Article  Google Scholar 

  6. Zeng C, Zhou Z, Han Y, Wen Z, Guo C, Huang S, et al. Interactions of TRAF6 and NLRX1 gene polymorphisms with environmental factors on the susceptibility of type 2 diabetes mellitus vascular complications in a southern Han Chinese population. J Diabetes Complicat. 2017;31(12):1652–7.

    Article  Google Scholar 

  7. Wu Y, Ding Y, Tanaka Y, Zhang W. Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention. Int J Med Sci. 2014;11(11):1185–200.

    Article  Google Scholar 

  8. Phani NM, Adhikari P, Nagri SK, D’Souza SC, Satyamoorthy K, Rai PS. Replication and relevance of multiple susceptibility loci discovered from genome wide association studies for type 2 diabetes in an Indian population. PLoS One. 2016;11(6):e0157364.

    Article  Google Scholar 

  9. Meybodi HRA, Hasanzad M, Larijani B. Path to personalized medicine for type 2 diabetes mellitus: reality and hope. Acta Med Iran. 2017:166–74.

  10. Xu P, Che Y, Cao Y, Wu X, Sun H, Liang F, et al. Polymorphisms of TCF7L2 and HHEX genes in Chinese women with polycystic ovary syndrome. J Assist Reprod Genet. 2010;27(1):23–8.

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  12. Lee Y-H, Kang ES, Kim SH, Han SJ, Kim CH, Kim HJ, 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.

    CAS  Article  Google Scholar 

  13. Lu CC, Chen YT, Chen SY, Hsu YM, Lin CC, Tsao JW, et al. Hematopoietically expressed homeobox gene is associated with type 2 diabetes in KK Cg-A(y)/J mice and a Taiwanese Han Chinese population. Exp Ther Med. 2018;16(1):185–91.

    PubMed  PubMed Central  Google Scholar 

  14. Wang Y, Qiao W, Zhao X, Tao M. Quantitative assessment of the influence of hematopoietically expressed homeobox variant (rs1111875) on type 2 diabetes risk. Mol Genet Metab. 2011;102(2):194–9.

    CAS  Article  Google Scholar 

  15. Association AD. Standards of medical care in diabetes—2017 abridged for primary care providers. Clinical diabetes: a publication of the American Diabetes Association. 2017;35(1):5.

    Article  Google Scholar 

  16. Miller S, Dykes D, Polesky H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215.

    CAS  Article  Google Scholar 

  17. Abdul-Hassan IA, Al-Tamimi MT, Al-dujaily SS. The association of HHEX gene polymorphism with the incidence of polycystic ovary syndrome (PCOS) in Iraq. World J Pharm Res. 2014;3(10):287–98.

    Google Scholar 

  18. Furukawa Y, Shimada T, Furuta H, Matsuno S, Kusuyama A, Doi A, et al. Polymorphisms in the IDE-KIF11-HHEX gene locus are reproducibly associated with type 2 diabetes in a Japanese population. J Clin Endocrinol Metab. 2008;93(1):310–4.

    CAS  Article  Google Scholar 

  19. Lin Y, Li P, Cai L, Zhang B, Tang X, Zhang X, et al. Association study of genetic variants in eight genes/loci with type 2 diabetes in a Han Chinese population. BMC Med Genet. 2010;11:97.

    Article  Google Scholar 

  20. Hu C, Zhang R, Wang C, Wang J, Ma X, Lu J, et al. 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.

    Article  Google Scholar 

  21. Chauhan G, Spurgeon CJ, Tabassum R, Bhaskar S, Kulkarni SR, Mahajan A, et al. 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.

    CAS  Article  Google Scholar 

  22. van Vliet-Ostaptchouk JV, Onland-Moret NC, van Haeften TW, Franke L, Elbers CC, Shiri-Sverdlov R, et al. HHEX gene polymorphisms are associated with type 2 diabetes in the Dutch Breda cohort. Eur J Hum Genet. 2008;16(5):652–6.

    Article  Google Scholar 

  23. Galavi H, Mollashahee-Kohkan F, Saravani R, Sargazi S, Noorzehi N, Shahraki H. HHEX gene polymorphisms and type 2 diabetes mellitus: a case-control report from Iran. J Cell Biochem. 2019;120(10):16445–51.

    CAS  Article  Google Scholar 

  24. Mansoori Y, Daraei A, Naghizadeh M, Salehi R. The HHEX rs1111875A/G gene polymorphism is associated with susceptibility to type 2 diabetes in the Iranian population. Mol Biol. 2015;49(4):535–42.

    CAS  Article  Google Scholar 

  25. Hassan HD. Iran: ethnic and religious minorities. LIBRARY OF CONGRESS WASHINGTON DC CONGRESSIONAL RESEARCH SERVICE.

  26. Sherwani SI, Khan HA, Ekhzaimy A, Masood A, Sakharkar MK. Significance of HbA1c test in diagnosis and prognosis of diabetic patients. Biomark Insights. 2016;11:BMI. S38440.

  27. Tabara Y, Osawa H, Kawamoto R, Onuma H, Shimizu I, Miki T, et al. Replication study of candidate genes associated with type 2 diabetes based on genome-wide screening. Diabetes. 2009;58(2):493–8.

    CAS  Article  Google Scholar 

  28. Wen J, Rönn T, Olsson A, Yang Z, Lu B, Du Y, et al. 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.

    Article  Google Scholar 

Download references

Acknowledgments

The researchers would like to express their gratitude to all participants enrolled in this project.

Author information

Authors and Affiliations

Authors

Contributions

MH managed the project and provided guidance to the research; PB and NS drafted the manuscript and performed lab genotyping; MA performed the statistical analysis; HRAM provided clinical guidance to the research.

All authors contributed to and approved the final version of the manuscript.

Corresponding authors

Correspondence to Hamid Reza Aghaei Meybodi or Mandana Hasanzad.

Ethics declarations

Ethical approval and consent to participate

This study was approved by Ethical committee (ID research ethics: IR.IAU.PS.REC.1398.031) and informed consent was obtained from all individual participants included in the study.

Competing interests

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Banihashemi, P., Aghaei Meybodi, H.R., Afshari, M. et al. Association analysis of HHEX gene variant with type 2 diabetes risk. Int J Diabetes Dev Ctries 41, 43–47 (2021). https://doi.org/10.1007/s13410-020-00870-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13410-020-00870-z

Keywords

  • HHEX
  • rs1111875
  • T2DM
  • Genetic variant