Skip to main content
SpringerLink
Log in

Associations of TMPRSS6 Polymorphisms with Gestational Diabetes Mellitus in Chinese Han Pregnant Women: a Preliminary Cohort Study

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Body iron status is likely to be associated with type 2 diabetes (T2DM) and gestational diabetes mellitus (GDM); transmembrane protease serine 6 (TMPRSS6) polymorphisms may be associated with T2DM risk through their effects on body iron status. However, it remains unknown whether the TMPRSS6 single nucleotide polymorphisms (SNPs) affect the risk of GDM development. We aimed to determine whether the TMPRSS6 SNPs rs855791 (V736A) and rs4820268 (D521D) are associated with the risk of GDM in pregnant women. The two SNPs in TMPRSS6 gene were genotyped and examined for their associations with body iron status and GDM risk in 398 unrelated Chinese Han pregnant women. The 2 TMPRSS6 SNPs rs855791 and rs4820268 were both significantly associated with serum iron and transferrin saturation (P < 0.01 for all) rather than ferritin. After adjustment for covariates, the C allele of rs4820268 was nominally and significantly associated with an increased risk of GDM (OR = 2.531; 95%CI = 1.044–6.136, P = 0.040); when concentrations of ferritin were further adjusted, the association was still significant (OR = 2.528; 95%CI = 1.043–6.126, P = 0.040). There was a significant trend (P = 0.065) in the association between the T allele of rs855791 and an increased GDM risk in this study population. The 2 TMPRSS6 SNPs rs855791 and rs4820268 were both significantly associated with serum iron and transferrin saturation, and TMPRSS6 variants might be associated with the risk of GDM. Furthermore, the effects of TMPRSS6 SNPs on the risk of GDM may not be completely explained by the mediation of body iron status. Further studies are warranted.

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

Fig. 1

Similar content being viewed by others

References

  1. Zhu Y, Zhang C (2016) Prevalence of gestational diabetes and risk of progression to type 2 diabetes: a global perspective. Curr Diab Rep 16:7

    PubMed  PubMed Central  Google Scholar 

  2. Hod M, Kapur A, Sacks DA, Hadar E, Agarwal M, di Renzo GC, Roura LC, McIntyre HD, Morris JL, Divakar H (2015) The International Federation of Gynecology and Obstetrics (FIGO) initiative on gestational diabetes mellitus: a pragmatic guide for diagnosis, management, and care. Int J Gynaecol Obstet 131(Suppl 3):S173–S211

    PubMed  Google Scholar 

  3. Lowe WL Jr, Scholtens DM, Kuang A et al (2019) Hyperglycemia and adverse pregnancy outcome follow-up study (HAPO FUS): maternal gestational diabetes mellitus and childhood glucose metabolism. Diabetes Care 42:372–380

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhao L, Lian J, Tian J, Shen Y, Ping Z, Fang X, Min J, Wang F (2017) Dietary intake of heme iron and body iron status are associated with the risk of gestational diabetes mellitus: a systematic review and meta-analysis. Asia Pac J Clin Nutr 26:1092–1106

    CAS  PubMed  Google Scholar 

  5. Fu S, Li F, Zhou J, Liu Z (2016) The relationship between body iron status, iron intake and gestational diabetes: a systematic review and meta-analysis. Medicine (Baltimore) 95:e2383

    Google Scholar 

  6. Zhang C, Rawal S (2017) Dietary iron intake, iron status, and gestational diabetes. Am J Clin Nutr 106(Suppl 6):1672S–1680S

    PubMed  PubMed Central  Google Scholar 

  7. Kataria Y, Wu Y, Horskjær PH et al (2018) Iron status and gestational diabetes-a meta-analysis. Nutrients 10:E621

    PubMed  Google Scholar 

  8. Koenig MD, Tussing-Humphreys L, Day J, Cadwell B, Nemeth E (2014) Hepcidin and iron homeostasis during pregnancy. Nutrients 6:3062–3083

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Fisher AL, Nemeth E (2017) Iron homeostasis during pregnancy. Am J Clin Nutr 106(Suppl 6):1567S–1574S

    PubMed  PubMed Central  Google Scholar 

  10. Bothwell TH (2000) Iron requirements in pregnancy and strategies to meet them. Am J Clin Nutr 72(Suppl 1):257S–264S

    CAS  PubMed  Google Scholar 

  11. Liu Q, Sun L, Tan Y, Wang G, Lin X, Cai L (2009) Role of iron deficiency and overload in the pathogenesis of diabetes and diabetic complications. Curr Med Chem 16:113–129

    CAS  PubMed  Google Scholar 

  12. Liu JM, Hankinson SE, Stampfer MJ, Rifai N, Willett WC, Ma J (2003) Body iron stores and their determinants in healthy postmenopausal US women. Am J Clin Nutr 78:1160–1167

    CAS  PubMed  Google Scholar 

  13. Wittenbecher C, Muhlenbruch K, Kroger J et al (2015) Amino acids, lipid metabolites, and ferritin as potential mediators linking red meat consumption to type 2 diabetes. Am J Clin Nutr 101:1241–1250

    CAS  PubMed  Google Scholar 

  14. Jiang R, Manson JE, Meigs JB et al (2004) Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. JAMA 291:711–717

    CAS  PubMed  Google Scholar 

  15. Fumeron F, Pean F, Driss F, Balkau B, Tichet J, Marre M, Grandchamp B, for the DESIR Study Group (2006) Ferritin and transferrin are both predictive of the onset of hyperglycemia in men and women over 3 years: the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Diabetes Care 29:2090–2094

    CAS  PubMed  Google Scholar 

  16. Jehn ML, Guallar E, Clark JM, Couper D, Duncan BB, Ballantyne CM, Hoogeveen RC, Harris ZL, Pankow JS (2007) A prospective study of plasma ferritin level and incident diabetes: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 165:1047–1054

    PubMed  Google Scholar 

  17. Forouhi NG, Harding AH, Allison M, Sandhu MS, Welch A, Luben R, Bingham S, Khaw KT, Wareham NJ (2007) Elevated serum ferritin levels predict new-onset type 2 diabetes: results from the EPIC-Norfolk prospective study. Diabetologia 50:949–956

    CAS  PubMed  Google Scholar 

  18. Ganz T (2005) Hepcidin--a regulator of intestinal iron absorption and iron recycling by macrophages. Best Pract Res Clin Haematol 18:171–182

    CAS  PubMed  Google Scholar 

  19. Nemeth E, Ganz T (2006) Regulation of iron metabolism by hepcidin. Annu Rev Nutr 26:323–342

    CAS  PubMed  Google Scholar 

  20. Whitfield JB, Cullen LM, Jazwinska EC, Powell LW, Heath AC, Zhu G, Duffy DL, Martin NG (2000) Effects of HFE C282Y and H63D polymorphisms and polygenic background on iron stores in a large community sample of twins. Am J Hum Genet 66:1246–1258

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Njajou OT, Alizadeh BZ, Aulchenko Y, Zillikens MC, Pols HAP, Oostra BA, Swinkels DW, van Duijn CM (2006) Heritability of serum iron, ferritin and transferrin saturation in a genetically isolated population, the Erasmus Rucphen Family (ERF) study. Hum Hered 61:222–228

    CAS  PubMed  Google Scholar 

  22. Marroni F, Grazio D, Pattaro C, Devoto M, Pramstaller P (2008) Estimates of genetic and environmental contribution to 43 quantitative traits support sharing of a homogeneous environment in an isolated population from South Tyrol, Italy. Hum Hered 65:175–182

    PubMed  Google Scholar 

  23. Pilia G, Chen WM, Scuteri A, Orrú M, Albai G, Dei M, Lai S, Usala G, Lai M, Loi P, Mameli C, Vacca L, Deiana M, Olla N, Masala M, Cao A, Najjar SS, Terracciano A, Nedorezov T, Sharov A, Zonderman AB, Abecasis GR, Costa P, Lakatta E, Schlessinger D (2006) Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet 2:e132

    PubMed  PubMed Central  Google Scholar 

  24. Soranzo N, Spector TD, Mangino M, Kühnel B, Rendon A, Teumer A, Willenborg C, Wright B, Chen L, Li M, Salo P, Voight BF, Burns P, Laskowski RA, Xue Y, Menzel S, Altshuler D, Bradley JR, Bumpstead S, Burnett MS, Devaney J, Döring A, Elosua R, Epstein SE, Erber W, Falchi M, Garner SF, Ghori MJR, Goodall AH, Gwilliam R, Hakonarson HH, Hall AS, Hammond N, Hengstenberg C, Illig T, König IR, Knouff CW, McPherson R, Melander O, Mooser V, Nauck M, Nieminen MS, O’Donnell CJ, Peltonen L, Potter SC, Prokisch H, Rader DJ, Rice CM, Roberts R, Salomaa V, Sambrook J, Schreiber S, Schunkert H, Schwartz SM, Serbanovic-Canic J, Sinisalo J, Siscovick DS, Stark K, Surakka I, Stephens J, Thompson JR, Völker U, Völzke H, Watkins NA, Wells GA, Wichmann HE, van Heel DA, Tyler-Smith C, Thein SL, Kathiresan S, Perola M, Reilly MP, Stewart AFR, Erdmann J, Samani NJ, Meisinger C, Greinacher A, Deloukas P, Ouwehand WH, Gieger C (2009) A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat GenetNat Genet 41:1182–1190

    CAS  Google Scholar 

  25. Ganesh SK, Zakai NA, van Rooij FJ et al (2009) Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nat Genet 41:1191–1198

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Benyamin B, Ferreira MA, Willemsen G et al (2009) Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat Genet 41:1173–1175

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Chambers JC, Zhang W, Li Y, Sehmi J, Wass MN, Zabaneh D, Hoggart C, Bayele H, McCarthy MI, Peltonen L, Freimer NB, Srai SK, Maxwell PH, Sternberg MJE, Ruokonen A, Abecasis G, Jarvelin MR, Scott J, Elliott P, Kooner JS (2009) Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nat Genet 41:1170–1172

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Nai A, Pagani A, Silvestri L, Camaschella C (2010) Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice. Blood 116:851–852

    CAS  PubMed  Google Scholar 

  29. Gan W, Guan Y, Wu Q, An P, Zhu J, Lu L, Jing L, Yu Y, Ruan S, Xie D, Makrides M, Gibson RA, Anderson GJ, Li H, Lin X, Wang F (2012) Association of TMPRSS6 polymorphisms with ferritin, hemoglobin, and type 2 diabetes risk in a Chinese Han population. Am J Clin Nutr 95:626–632

    CAS  PubMed  Google Scholar 

  30. Meidtner K, Podmore C, Kroger J et al (2018) Interaction of dietary and genetic factors influencing body iron status and risk of type 2 diabetes within the EPIC-InterAct study. Diabetes Care 41:277–285

    CAS  PubMed  Google Scholar 

  31. He M, Workalemahu T, Manson JE, Hu FB, Qi L (2012) Genetic determinants for body iron store and type 2 diabetes risk in US men and women. PLoS One 7:e40919

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhu WW, Yang HX, Wei YM, Yan J, Wang ZL, Li XL, Wu HR, Li N, Zhang MH, Liu XH, Zhang H, Wang YH, Niu JM, Gan YJ, Zhong LR, Wang YF, Kapur A (2013) Evaluation of the value of fasting plasma glucose in the first prenatal visit to diagnose gestational diabetes mellitus in China. Diabetes Care 36:586–590

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Deputy NP, Kim SY, Conrey EJ, Bullard KM (2018) Prevalence and changes in preexisting diabetes and gestational diabetes among women who had a live birth - United States, 2012-2016. MMWR Morb Mortal Wkly Rep 67:1201–1207

    PubMed  PubMed Central  Google Scholar 

  34. Eades CE, Cameron DM, Evans JMM (2017) Prevalence of gestational diabetes mellitus in Europe: a meta-analysis. Diabetes Res Clin Pract 129:173–181

    PubMed  Google Scholar 

  35. Coad J, Conlon C (2011) Iron deficiency in women: assessment, causes and consequences. Curr Opin Clin Nutr Metab Care 14:625–634

    CAS  PubMed  Google Scholar 

  36. Rahman MM, Abe SK, Rahman MS, Kanda M, Narita S, Bilano V, Ota E, Gilmour S, Shibuya K (2016) Maternal anemia and risk of adverse birth and health outcomes in low- and middle-income countries: systematic review and meta-analysis. Am J Clin Nutr 103:495–504

    CAS  PubMed  Google Scholar 

  37. Zein S, Rachidi S, Awada S, Osman M, al-Hajje A, Shami N, Sharara I, Cheikh-Ali K, Salameh P, Hininger-Favier I (2015) High iron level in early pregnancy increased glucose intolerance. J Trace Elem Med Biol 30:220–225

    CAS  PubMed  Google Scholar 

  38. Sun C, Wu QJ, Gao SY, Ma ZM, Liu YS, Zhang JY, Zhao YH (2019) Association between the ferritin level and risk of gestational diabetes mellitus: a meta-analysis of observational studies. J Diabetes Investig 31. https://doi.org/10.1111/jdi.13170

  39. Tanaka T, Roy CN, Yao W, Matteini A, Semba RD, Arking D, Walston JD, Fried LP, Singleton A, Guralnik J, Abecasis GR, Bandinelli S, Longo DL, Ferrucci L (2010) A genome-wide association analysis of serum iron concentrations. Blood 115:94–96

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Pichler I, Minelli C, Sanna S, Tanaka T, Schwienbacher C, Naitza S, Porcu E, Pattaro C, Busonero F, Zanon A, Maschio A, Melville SA, Grazia Piras M, Longo DL, Guralnik J, Hernandez D, Bandinelli S, Aigner E, Murphy AT, Wroblewski V, Marroni F, Theurl I, Gnewuch C, Schadt E, Mitterer M, Schlessinger D, Ferrucci L, Witcher DR, Hicks AA, Weiss G, Uda M, Pramstaller PP (2011) Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels. Hum Mol Genet 20:1232–1240

    CAS  PubMed  Google Scholar 

  41. Camaschella C (2015) Iron deficiency: new insights into diagnosis and treatment. Hematol Am Soc Hematol Educ Program 2015:8–13

    Google Scholar 

  42. Green A, Basile R, Rumberger JM (2006) Transferrin and iron induce insulin resistance of glucose transport in adipocytes. Metabolism 55:1042–1045

    CAS  PubMed  Google Scholar 

  43. Brewster JA, Orsi NM, Gopichandran N, McShane P, Ekbote UV, Walker JJ (2008) Gestational effects on host inflammatory response in normal and preeclamptic pregnancies. Eur J Obstet Gynecol Reprod Biol 140:21–26

    PubMed  Google Scholar 

Download references

Acknowledgments

We thank Shanghai GeneX Biotech Co., Ltd., for its free genetic measurements as well as to Ma Shuai and Hou Li An for their technical support.

Author Contributions Statement

L.Y., M.L., and L.P.J: designed the research; L.P.J, L.Y., M.L., and Y.A.: conducted the data analysis; L.P.J, C.X.Y, and H.Y.X: reviewed the research plan and manuscript; and L.P.J, L.Y., M.L., and H.Y.X: wrote the manuscript. None of the authors declared any competing interests.

Author information

Authors and Affiliations

  1. The Department of Clinical Nutrition, Peking Union Medical College Hospital, China Academic Medical Science and Peking Union Medical College, Beijing, People’s Republic of China

    Peng Ju Liu & Yanping Liu

  2. The Department of Gynaecology and Obstetrics, Shunyi Women’s and Children’s Hospital, Beijing, People’s Republic of China

    Aimin Yao

  3. The Department of Gynaecology and Obstetrics, Quanzhou Maternal and Child Health Hospital, Quanzhou, Fujian, People’s Republic of China

    Xiao Yan Chen

  4. Department of Gynaecology and Obstetrics, Peking Union Medical College Hospital, China Academic Medical Science and Peking Union Medical College, Beijing, People’s Republic of China

    Liangkun Ma

  5. School of Nursing, Peking Union Medical College, Beijing, People’s Republic of China

    Yi Xuan Hou

Authors
  1. Peng Ju Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aimin Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao Yan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanping Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Liangkun Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi Xuan Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yanping Liu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethnic Approval

The study protocol was approved by the Ethics Committee of Peking Union Medical College Hospital of the Chinese Academy of Medical Science (Unique Protocol ID: hs-1646). This study was conducted in accordance with both the Declaration of Helsinki of 1975, as revised in 1983, and guidelines of the center’s institutional review board.

Consent to Participate

All the participants were informed of the details of the study, and each participant provided written informed consent.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, P.J., Yao, A., Chen, X.Y. et al. Associations of TMPRSS6 Polymorphisms with Gestational Diabetes Mellitus in Chinese Han Pregnant Women: a Preliminary Cohort Study. Biol Trace Elem Res 199, 473–481 (2021). https://doi.org/10.1007/s12011-020-02169-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-020-02169-w

Keywords

Search

Navigation