Skip to main content
SpringerLink
Log in

Gender differences in the association of ELMO1 genetic variants with type 2 diabetes in Tunisian Arabs

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Purpose

Polymorphisms of the engulfment and cell motility 1 (ELMO1) gene were recently associated with type 2 diabetes (T2DM) and its complications. We investigated the association of rs10255208, rs7782979, and rs2041801 ELMO1 gene variants with T2DM in Tunisian Arabs.

Methods

Subjects comprised 900 T2DM patients and 600 normoglycemic controls. ELMO1 genotyping was done by PCR–RFLP; the contribution of ELMO1 variants to T2DM was analyzed by Haploview and regression analysis.

Results

Minor allele frequencies of rs7782979 and rs10255208 ELMO1 variants were significantly higher among unselected T2DM cases than controls, and significant differences in the distribution of rs7782979 genotypes were seen between T2DM cases and control subjects, which was seen in male but not female subjects. Three-locus ELMO1 haplotype analysis identified haplotype GAA to be positively associated, and haplotypes GCA, AAA, and GCG to be negatively associated with T2DM. The distribution of these haplotypes was gender-dependent for some (GCA, GCG, AAG), and gender-independent for others (GAA, AAA). This translated into altered risk of T2DM in male or female subjects, which persisted after adjusting for BMI, systolic and diastolic blood pressure, and serum lipid profile.

Conclusion

These results confirm role for ELMO1 as T2DM susceptibility locus, which appears to be gender-dependent.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

DN:

Diabetic nephropathy

ELMO1 :

Engulfment and cell motility 1

GWAS:

Genome-wide association studies

LD:

Linkage disequilibrium

MAF:

Minor allele frequency

T2DM:

Type 2 diabetes

References

  1. Bell GI, Polonsky KS (2001) Diabetes mellitus and genetically programmed defects in β-cell function. Nature 414:788–791

    Article  CAS  PubMed  Google Scholar 

  2. Kahn SE, Hull RL, Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840–846

    Article  CAS  PubMed  Google Scholar 

  3. Tao Z, Shi A, Zhao J (2015) Epidemiological perspectives of diabetes. Cell Biochem Biophys 73:181–185

    Article  CAS  PubMed  Google Scholar 

  4. Saidi O, O’Flaherty M, Mansour NB, Aissi W, Lassoued O, Capewell S et al (2015) Forecasting Tunisian type 2 diabetes prevalence to 2027: validation of a simple model. BMC Public Health 15:104

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jenum AK, Holme I, Graff-Iversen S, Birkeland KI (2005) Ethnicity and sex are strong determinants of diabetes in an urban Western society: implications for prevention. Diabetologia 48:435–439

    Article  CAS  PubMed  Google Scholar 

  6. Temelkova-Kurktschiev T, Stefanov T (2012) Lifestyle and genetics in obesity and type 2 diabetes. Exp Clin Endocrinol Diabetes 120:1–6

    Article  CAS  PubMed  Google Scholar 

  7. Legato MJ, Gelzer A, Goland R, Ebner SA, Rajan S, Villagra V et al (2006) Gender-specific care of the patient with diabetes: review and recommendations. Gend Med 3:131–158

    Article  PubMed  Google Scholar 

  8. Regitz-Zagrosek V, Lehmkuhl E, Weickert MO (2006) Gender differences in the metabolic syndrome and their role for cardiovascular disease. Clin Res Cardiol 95:136–147

    Article  CAS  PubMed  Google Scholar 

  9. Franconi F, Seghieri G, Canu S, Straface E, Campesi I, Malorni W (2008) Are the available experimental models of type 2 diabetes appropriate for a gender perspective. Pharmacol Res 57:6–18

    Article  PubMed  Google Scholar 

  10. Buday B, Pach PF, Literati-Nagy B, Vitai M, Kovacs G, Vecsei Z et al (2015) Sex influenced association of directly measured insulin sensitivity and serum transaminase levels: why alanine aminotransferase only predicts cardiovascular risk in men? Cardiovasc Diabetol. 14:55

    Article  PubMed  PubMed Central  Google Scholar 

  11. Johar H, Emeny RT, Bidlingmaier M, Kruse J, Ladwig KH (2016) Sex-related differences in the association of salivary cortisol levels and type 2 diabetes. Findings from the cross-sectional population based KORA-age study. Psychoneuroendocrinol 69:133–141

    Article  CAS  Google Scholar 

  12. Imamura M, Maeda S (2011) Genetics of type 2 diabetes: the GWAS era and future perspectives. Endocr J 58:723–739

    Article  CAS  PubMed  Google Scholar 

  13. McCarthy MI, Zeggini E (2009) Genome-wide association studies in type 2 diabetes. Curr Diab Rep 9:164–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shimazaki A, Kawamura Y, Kanazawa A, Sekine A, Saito S, Tsunoda T et al (2005) Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy. Diabetes 54:1171–1178

    Article  CAS  PubMed  Google Scholar 

  15. Leak TS, Perlegas PS, Smith SG, Keene KL, Hicks PJ, Langefeld CD et al (2009) Variants in intron 13 of the ELMO1 gene are associated with diabetic nephropathy in African Americans. Ann Hum Genet 73:152–159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hanson RL, Millis MP, Young NJ, Kobes S, Nelson RG, Knowler WC et al (2010) ELMO1 variants and susceptibility to diabetic nephropathy in American Indians. Mol Gen Metab 101:383–390

    Article  CAS  Google Scholar 

  17. Craig DW, Millis MP, DiStefano JK (2009) Genome-wide SNP genotyping study using pooled DNA to identify candidate markers mediating susceptibility to end-stage renal disease attributed to Type 1 diabetes. Diabet Med 26:1090–1098

    Article  CAS  PubMed  Google Scholar 

  18. Pezzolesi MG, Katavetin P, Kure M, Poznik GD, Skupien J, Mychaleckyj JC et al (2009) Confirmation of genetic associations at ELMO1 in the GoKinD collection supports its role as a susceptibility gene in diabetic nephropathy. Diabetes 58:2698–2702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu HY, Wang Y, Chen M, Zhang X, Wang D, Pan Y et al (2013) Association of ELMO1 gene polymorphisms with diabetic nephropathy in Chinese population. J Endocrinol Invest 36:298–302

    CAS  PubMed  Google Scholar 

  20. Placha G, Poznik GD, Dunn J, Smiles A, Krolewski B, Glew T et al (2006) A genome-wide linkage scan for genes controlling variation in renal function estimated by serum cystatin C levels in extended families with type 2 diabetes. Diabetes 55:3358–3365

    Article  CAS  PubMed  Google Scholar 

  21. De Bakker CD, Haney LB, Kinchen JM, Grimsley C, Lu M, Klingele D et al (2004) Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO. Curr Biol 14:2208–2216

    Article  Google Scholar 

  22. Gumienny TL, Brugnera E, Tosello-Trampont AC, Kinchen JM, Haney LB, Nishiwaki K et al (2001) CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell 107:27–41

    Article  CAS  PubMed  Google Scholar 

  23. Grimsley CM, Kinchen JM, Tosello-Trampont AC, Brugnera E, Haney LB, Lu M et al (2004) Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration. J Biol Chem 279:6087–6097

    Article  CAS  PubMed  Google Scholar 

  24. Yokoyama N, deBakker CD, Zappacosta F, Huddleston MJ, Annan RS, Ravichandran KS et al (2005) Identification of tyrosine residues on ELMO1 that are phosphorylated by the Src-family kinase Hck. Biochemistry 44:8841–8849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sanui T, Inayoshi A, Noda M, Iwata E, Stein JV, Sasazuki T et al (2003) DOCK2 regulates Rac activation and cytoskeletal reorganization through interaction with ELMO1. Blood 102:2948–2950

    Article  CAS  PubMed  Google Scholar 

  26. Janardhan A, Swigut T, Hill B, Myers MP, Skowronski J (2004) HIV-1 Nef binds the DOCK2-ELMO1 complex to activate rac and inhibit lymphocyte chemotaxis. PLoS Biol 2:E6

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chang YC, Chang EY, Chuang LM (2015) Recent progress in the genetics of diabetic microvascular complications. World J Diabetes 6:715–725

    Article  PubMed  PubMed Central  Google Scholar 

  28. Shimazaki A, Tanaka Y, Shinosaki T, Ikeda M, Watada H, Hirose T et al (2006) ELMO1 increases expression of extracellular matrix proteins and inhibits cell adhesion to ECMs. Kidney Int 70:1769–1776

    Article  CAS  PubMed  Google Scholar 

  29. Ryoo H, Woo J, Kim Y, Lee C (2011) Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender. Eur J Hum Genet 19:672–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Linder K, Wagner R, Hatziagelaki E, Ketterer C, Heni M, Machicao F et al (2012) Allele summation of diabetes risk genes predicts impaired glucose tolerance in female and obese individuals. PLoS One 7:e38224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Turki A, Al-Zaben GS, Khirallah M, Marmouch H, Mahjoub T, Almawi WY (2014) Gender-dependent associations of CDKN2A/2B, KCNJ11, POLI, SLC30A8, and TCF7L2 variants with type 2 diabetes in (North African) Tunisian Arabs. Diabetes Res Clin Pract 103:e40–e43

    Article  CAS  PubMed  Google Scholar 

  32. Hammami S, Mehri S, Hajem S, Koubaa N, Souid H, Hammami M (2012) Prevalence of diabetes mellitus among non institutionalized elderly in Monastir City. BMC Endocr Disord 16:12–15

    Google Scholar 

  33. Qiao Q, Hu G, Tuomilehto J, Nakagami T, Balkau B, Borch- Johnsen K et al (2003) Age- and sex-specific prevalence of diabetes and impaired glucose regulation in 11 Asian cohorts. Diabetes Care 26:1770–1780

    Article  PubMed  Google Scholar 

  34. Grossmann M, Thomas MC, Panagiotopoulos S, Sharpe K, Macisaac RJ, Clarke S et al (2008) Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab 93:1834–1840

    Article  CAS  PubMed  Google Scholar 

  35. Talaei A, Amini M, Siavash M, Zare M (2010) The effect of dehydroepiandrosterone on insulin resistance in patients with impaired glucose tolerance. Hormones (Athens) 9:326–331

    Article  Google Scholar 

  36. Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC et al (2002) Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex. Nat Cell Biol 4:574–582

    Article  CAS  PubMed  Google Scholar 

  37. Hathaway CK, Chang AS, Grant R, Kim HS, Madden VJ, Bagnell CR Jr et al (2016) High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy. Proc Natl Acad Sci USA 113:2218–2222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Laboratory of Human Genome and Multifactorial Diseases, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia

    A. Turki, S. Mzoughi, N. Mtitaoui & T. Mahjoub

  2. Higher Institute of Biotechnology of Monastir, Monastir, Tunisia

    N. Mtitaoui

  3. Department of Ophthalmology, Fattouma Bourguiba University Hospital, Monastir, Tunisia

    M. Khairallah

  4. Department of Endocrinology and Internal Medicine, Fattouma Bourguiba University Hospital, Monastir, Tunisia

    H. Marmouch & S. Hammami

  5. Faculty of Sciences, El Manar University, Tunis, Tunisia

    W. Y. Almawi

Authors
  1. A. Turki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Mzoughi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Mtitaoui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Khairallah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. Marmouch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Hammami
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T. Mahjoub
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. W. Y. Almawi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W. Y. Almawi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest with the article.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in this study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Turki, A., Mzoughi, S., Mtitaoui, N. et al. Gender differences in the association of ELMO1 genetic variants with type 2 diabetes in Tunisian Arabs. J Endocrinol Invest 41, 285–291 (2018). https://doi.org/10.1007/s40618-017-0734-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-017-0734-7

Keywords

Search

Navigation