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Genetic Studies of Gestational Diabetes and Glucose Metabolism in Pregnancy

  • Genetics (AP Morris, Section Editor)
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Abstract

Purpose of Review

In this review, we summarize studies investigating genetics of gestational diabetes mellitus (GDM) and glucose metabolism in pregnancy. We describe these studies in the context of the larger body of literature on type 2 diabetes (T2D) and glycemic trait genomics.

Recent Findings

We reviewed 23 genetic association studies for GDM and performed a meta-analysis, which revealed variants at eight T2D loci significantly associated with GDM after the Bonferroni correction. These studies suggest that GDM and T2D share a number of genetic risk loci. Only two unbiased genome-wide association studies (GWASs) have successfully revealed genetic associations for GDM and related glycemic traits in pregnancy. A GWAS for GDM in Korean women identified two loci (near CDKAL1 and MTNR1B) known to be associated with T2D, though the association of the MTNR1B locus with GDM appears to be stronger than that for T2D. A multi-ethnic GWAS for glycemic traits in pregnancy identified two novel loci (near HKDC1 and BACE2) which appear to be associated with post-load glucose and fasting c-peptide specifically in pregnant women. There are ongoing efforts to use this genetic information, in the form of polygenic scores, to predict risk of GDM and postpartum T2D.

Summary

The body of literature examining genetic associations with GDM is limited, especially when compared to the available literature on T2D and glycemic trait genomics. Additional genetic discovery for glucose metabolism in pregnant women will require larger pregnancy cohorts and international collaborative efforts. Studies on the clinical implications of these findings are also warranted.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Hapo Study Cooperative Research Group, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;58(19):1991–2002. https://doi.org/10.1056/NEJMoa0707943.

    Article  Google Scholar 

  2. Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey B, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;361(14):1339–48. https://doi.org/10.1056/NEJMoa0902430.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352(24):2477–86.

    Article  CAS  PubMed  Google Scholar 

  4. Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 190: Gestational diabetes mellitus. Obstet Gynecol. 2018;131(2):e49–64. https://doi.org/10.1097/AOG.0000000000002501.

    Article  Google Scholar 

  5. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S14–31. https://doi.org/10.2337/dc20-S002.

    Article  Google Scholar 

  6. Buchanan TA, Xiang AH, Page KA. Gestational diabetes mellitus: risks and management during and after pregnancy. Nat Rev Endocrinol. 2012;8(11):639–49. https://doi.org/10.1038/nrendo.2012.96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Buchanan TA, Xiang A, Kjos SL, Watanabe R. What is gestational diabetes? Diabetes Care. 2007;30(Suppl 2):S105–11. https://doi.org/10.2337/dc07-s201.

    Article  CAS  PubMed  Google Scholar 

  8. Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol. 1991;165(6 Pt 1):1667–72.

    Article  CAS  PubMed  Google Scholar 

  9. Catalano PM, Tyzbir ED, Wolfe RR, Calles J, Roman NM, Amini SB, et al. Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes. Am J Phys. 1993;264(1 Pt 1):E60–7.

    CAS  Google Scholar 

  10. Ryan EA, O'Sullivan MJ, Skyler JS. Insulin action during pregnancy. Studies with the euglycemic clamp technique. Diabetes. 1985;34(4):380–9.

    Article  CAS  PubMed  Google Scholar 

  11. Buchanan TA, Metzger BE, Freinkel N, Bergman RN. Insulin sensitivity and B-cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes. Am J Obstet Gynecol. 1990;162(4):1008–14.

    Article  CAS  PubMed  Google Scholar 

  12. Powe CE, Huston Presley LP, Locascio JJ, Catalano PM. Augmented insulin secretory response in early pregnancy. Diabetologia. 2019;62(8):1445–52. https://doi.org/10.1007/s00125-019-4881-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care. 2002;25(10):1862–8.

    Article  PubMed  Google Scholar 

  14. Kwak SH, Choi SH, Jung HS, Cho YM, Lim S, Cho NH, et al. Clinical and genetic risk factors for type 2 diabetes at early or late post partum after gestational diabetes mellitus. J Clin Endocrinol Metab. 2013;98(4):E744–52. https://doi.org/10.1210/jc.2012-3324.

    Article  CAS  PubMed  Google Scholar 

  15. Schwartz N, Nachum Z, Green MS. The prevalence of gestational diabetes mellitus recurrence--effect of ethnicity and parity: a metaanalysis. Am J Obstet Gynecol. 2015;213(3):310–7. https://doi.org/10.1016/j.ajog.2015.03.011.

    Article  PubMed  Google Scholar 

  16. Kwak SH, Kim HS, Choi SH, Lim S, Cho YM, Park KS, et al. Subsequent pregnancy after gestational diabetes mellitus: frequency and risk factors for recurrence in Korean women. Diabetes Care. 2008;31(9):1867–71. https://doi.org/10.2337/dc08-0384.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Rauh-Hain JA, Rana S, Tamez H, Wang A, Cohen B, Cohen A, et al. Risk for developing gestational diabetes in women with twin pregnancies. J Matern Fetal Neonatal Med. 2009;22(4):293–9. https://doi.org/10.1080/14767050802663194.

    Article  PubMed  Google Scholar 

  18. Vujkovic M, Keaton JM, Lynch JA, Miller DR, Zhou J, Tcheandjieu C, et al. 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. 2020;52(7):680–91. https://doi.org/10.1038/s41588-020-0637-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shaat N, Karlsson E, Lernmark A, Ivarsson S, Lynch K, Parikh H, et al. Common variants in MODY genes increase the risk of gestational diabetes mellitus. Diabetologia. 2006;49(7):1545–51. https://doi.org/10.1007/s00125-006-0258-8.

    Article  CAS  PubMed  Google Scholar 

  20. Shaat N, Groop L. Genetics of gestational diabetes mellitus. Curr Med Chem. 2007;14(5):569–83. https://doi.org/10.2174/092986707780059643.

    Article  CAS  PubMed  Google Scholar 

  21. Shaat N, Ekelund M, Lernmark A, Ivarsson S, Almgren P, Berntorp K, et al. Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus. Diabetologia. 2005;48(12):2544–51. https://doi.org/10.1007/s00125-005-0035-0.

    Article  CAS  PubMed  Google Scholar 

  22. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006;38(3):320–3. https://doi.org/10.1038/ng1732.

    Article  CAS  PubMed  Google Scholar 

  23. Shaat N, Lernmark A, Karlsson E, Ivarsson S, Parikh H, Berntorp K, et al. A variant in the transcription factor 7-like 2 (TCF7L2) gene is associated with an increased risk of gestational diabetes mellitus. Diabetologia. 2007;50(5):972–9. https://doi.org/10.1007/s00125-007-0623-2.

    Article  CAS  PubMed  Google Scholar 

  24. Watanabe RM, Allayee H, Xiang AH, Trigo E, Hartiala J, Lawrence JM, et al. Transcription factor 7-like 2 (TCF7L2) is associated with gestational diabetes mellitus and interacts with adiposity to alter insulin secretion in Mexican Americans. Diabetes. 2007;56(5):1481–5. https://doi.org/10.2337/db06-1682.

    Article  CAS  PubMed  Google Scholar 

  25. 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. https://doi.org/10.1038/nature05616.

    Article  CAS  PubMed  Google Scholar 

  26. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007;316(5829):1336–41. https://doi.org/10.1126/science.1142364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007;316(5829):1341–5. https://doi.org/10.1126/science.1142382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Diabetes Genetics Initiative of Broad Institute of H, Mit LU, Novartis Institutes of BioMedical R, Saxena R, Voight BF, Lyssenko V, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316(5829):1331–6. https://doi.org/10.1126/science.1142358.

    Article  CAS  Google Scholar 

  29. •• Lauenborg J, Grarup N, Damm P, Borch-Johnsen K, Jørgensen T, Pedersen O, et al. Common type 2 diabetes risk gene variants associate with gestational diabetes. J Clin Endocrinol Metab. 2009;94(1):145–50. https://doi.org/10.1210/jc.2008-1336. One of the early studies to investigate T2D GWAS loci for its association with GDM.

    Article  CAS  PubMed  Google Scholar 

  30. •• Cho YM, Kim TH, Lim S, Choi SH, Shin HD, Lee HK, et al. Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population. Diabetologia. 2009;52(2):253–61. https://doi.org/10.1007/s00125-008-1196-4. One of the early studies to investigate T2D GWAS loci for its association with GDM.

    Article  CAS  PubMed  Google Scholar 

  31. Huopio H, Cederberg H, Vangipurapu J, Hakkarainen H, Paakkonen M, Kuulasmaa T, et al. Association of risk variants for type 2 diabetes and hyperglycemia with gestational diabetes. Eur J Endocrinol. 2013;169(3):291–7. https://doi.org/10.1530/EJE-13-0286.

    Article  CAS  PubMed  Google Scholar 

  32. Kawai VK, Levinson RT, Adefurin A, Kurnik D, Collier SP, Conway D, et al. A genetic risk score that includes common type 2 diabetes risk variants is associated with gestational diabetes. Clin Endocrinol. 2017;87(2):149–55. https://doi.org/10.1111/cen.13356.

    Article  CAS  Google Scholar 

  33. Rosta K, Al-Aissa Z, Hadarits O, Harreiter J, Nádasdi Á, Kelemen F, et al. Association study with 77 SNPs confirms the robust role for the rs10830963/G of MTNR1B variant and identifies two novel associations in gestational diabetes mellitus development. PLoS One. 2017;12(1):e0169781. https://doi.org/10.1371/journal.pone.0169781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tarnowski M, Malinowski D, Safranow K, Dziedziejko V, Pawlik A. MTNR1A and MTNR1B gene polymorphisms in women with gestational diabetes. Gynecol Endocrinol. 2017;33(5):395–8. https://doi.org/10.1080/09513590.2016.1276556.

    Article  CAS  PubMed  Google Scholar 

  35. Tarnowski M, Malinowski D, Pawlak K, Dziedziejko V, Safranow K, Pawlik A. GCK, GCKR, FADS1, DGKB/TMEM195 and CDKAL1 gene polymorphisms in women with gestational diabetes. Can J Diabetes. 2017;41(4):372–9. https://doi.org/10.1016/j.jcjd.2016.11.009.

    Article  PubMed  Google Scholar 

  36. Tarnowski M, Malinowski D, Safranow K, Dziedziejko V, Czerewaty M, Pawlik A. Hematopoietically expressed homeobox (HHEX) gene polymorphism (rs5015480) is associated with increased risk of gestational diabetes mellitus. Clin Genet. 2017;91(6):843–8. https://doi.org/10.1111/cge.12875.

    Article  CAS  PubMed  Google Scholar 

  37. Tarnowski M, Malinowski D, Safranow K, Dziedziejko V, Pawlik A. CDC123/CAMK1D gene rs12779790 polymorphism and rs10811661 polymorphism upstream of the CDKN2A/2B gene in women with gestational diabetes. J Perinatol. 2017;37(4):345–8. https://doi.org/10.1038/jp.2016.249.

    Article  CAS  PubMed  Google Scholar 

  38. Ding M, Chavarro J, Olsen S, Lin Y, Ley SH, Bao W, et al. Genetic variants of gestational diabetes mellitus: a study of 112 SNPs among 8722 women in two independent populations. Diabetologia. 2018;61(8):1758–68. https://doi.org/10.1007/s00125-018-4637-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tarnowski M, Malinowski D, Safranow K, Dziedziejko V, Pawlik A. HNF1B, TSPAN8 and NOTCH2 gene polymorphisms in women with gestational diabetes. J Matern Fetal Neonatal Med. 2018;31(7):837–42. https://doi.org/10.1080/14767058.2017.1297793.

    Article  CAS  PubMed  Google Scholar 

  40. Tarnowski M, Bujak J, Kopytko P, Majcher S, Ustianowski P, Dziedziejko V, et al. Effect of FTO and IGF2BP2 gene polymorphisms on duration of pregnancy and Apgar scores in women with gestational diabetes. J Obstet Gynaecol. 2019;39(2):151–6. https://doi.org/10.1080/01443615.2018.1502263.

    Article  CAS  PubMed  Google Scholar 

  41. Wang Y, Nie M, Li W, Ping F, Hu Y, Ma L, et al. Association of six single nucleotide polymorphisms with gestational diabetes mellitus in a Chinese population. PLoS One. 2011;6(11):e26953. https://doi.org/10.1371/journal.pone.0026953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. •• Kwak SH, Kim SH, Cho YM, Go MJ, Cho YS, Choi SH, et al. A genome-wide association study of gestational diabetes mellitus in Korean women. Diabetes. 2012;61(2):531–41. https://doi.org/10.2337/db11-1034. This is the first GWAS to investigate genetic risk factors on GDM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li C, Qiao B, Zhan Y, Peng W, Chen ZJ, Sun L, et al. Association between genetic variations in MTNR1A and MTNR1B genes and gestational diabetes mellitus in Han Chinese women. Gynecol Obstet Investig. 2013;76(4):221–7. https://doi.org/10.1159/000355521.

    Article  CAS  Google Scholar 

  44. Liu Q, Huang Z, Li H, Bai J, Liu X, Ye H. Relationship between melatonin receptor 1B (rs10830963 and rs1387153) with gestational diabetes mellitus: a case-control study and meta-analysis. Arch Gynecol Obstet. 2016;294(1):55–61. https://doi.org/10.1007/s00404-015-3948-y.

    Article  CAS  PubMed  Google Scholar 

  45. Kasuga Y, Hata K, Tajima A, Ochiai D, Saisho Y, Matsumoto T, et al. Association of common polymorphisms with gestational diabetes mellitus in Japanese women: a case-control study. Endocr J. 2017;64(4):463–75. https://doi.org/10.1507/endocrj.EJ16-0431.

    Article  CAS  PubMed  Google Scholar 

  46. Cao M, Zhang L, Chen T, Shi A, Xie K, Li Z, et al. Genetic susceptibility to gestational diabetes mellitus in a Chinese population. Front Endocrinol (Lausanne). 2020;11:247. https://doi.org/10.3389/fendo.2020.00247.

    Article  Google Scholar 

  47. Ren J, Xiang AH, Trigo E, Takayanagi M, Beale E, Lawrence JM, et al. Genetic variation in MTNR1B is associated with gestational diabetes mellitus and contributes only to the absolute level of beta cell compensation in Mexican Americans. Diabetologia. 2014;57(7):1391–9. https://doi.org/10.1007/s00125-014-3239-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kanthimathi S, Chidambaram M, Liju S, Bhavadharini B, Bodhini D, Prakash VG, et al. Identification of genetic variants of gestational diabetes in South Indians. Diabetes Technol Ther. 2015;17(7):462–7. https://doi.org/10.1089/dia.2014.0349.

    Article  CAS  PubMed  Google Scholar 

  49. Arora GP, Almgren P, Brøns C, Thaman RG, Vaag AA, Groop L, et al. Association between genetic risk variants and glucose intolerance during pregnancy in north Indian women. BMC Med Genet. 2018;11(1):64. https://doi.org/10.1186/s12920-018-0380-8.

    Article  CAS  Google Scholar 

  50. Alharbi KK, Al-Sulaiman AM, Shedaid KMB, Al-Shangiti AM, Marie M, Al-Sheikh YA, et al. MTNR1B genetic polymorphisms as risk factors for gestational diabetes mellitus: a case-control study in a single tertiary care center. Ann Saudi Med. 2019;39(5):309–18. https://doi.org/10.5144/0256-4947.2019.309.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Huerta-Chagoya A, Vázquez-Cárdenas P, Moreno-Macías H, Tapia-Maruri L, Rodríguez-Guillén R, López-Vite E, et al. Genetic determinants for gestational diabetes mellitus and related metabolic traits in Mexican women. PLoS One. 2015;10(5):e0126408. https://doi.org/10.1371/journal.pone.0126408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pulit SL, Stoneman C, Morris AP, Wood AR, Glastonbury CA, Tyrrell J, et al. Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry. Hum Mol Genet. 2019;28(1):166–74. https://doi.org/10.1093/hmg/ddy327.

    Article  CAS  PubMed  Google Scholar 

  53. Wu NN, Zhao D, Ma W, Lang JN, Liu SM, Fu Y, et al. A genome-wide association study of gestational diabetes mellitus in Chinese women. J Matern Fetal Neonatal Med. 2019:1–8. https://doi.org/10.1080/14767058.2019.1640205.

  54. Bouatia-Naji N, Bonnefond A, Cavalcanti-Proenca C, Sparso T, Holmkvist J, Marchand M, et al. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet. 2009;41(1):89–94. https://doi.org/10.1038/ng.277.

    Article  CAS  PubMed  Google Scholar 

  55. Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, et al. Variants in MTNR1B influence fasting glucose levels. Nat Genet. 2009;41(1):77–81. https://doi.org/10.1038/ng.290.

    Article  CAS  PubMed  Google Scholar 

  56. Lyssenko V, Nagorny CL, Erdos MR, Wierup N, Jonsson A, Spegel P, et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet. 2009;41(1):82–8. https://doi.org/10.1038/ng.288.

    Article  CAS  PubMed  Google Scholar 

  57. Jonsson A, Ladenvall C, Ahluwalia TS, Kravic J, Krus U, Taneera J, et al. Effects of common genetic variants associated with type 2 diabetes and glycemic traits on alpha- and beta-cell function and insulin action in humans. Diabetes. 2013;62(8):2978–83. https://doi.org/10.2337/db12-1627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wood AR, Jonsson A, Jackson AU, Wang N, van Leewen N, Palmer ND, et al. A genome-wide association study of IVGTT-based measures of first-phase insulin secretion refines the underlying physiology of type 2 diabetes variants. Diabetes. 2017;66(8):2296–309. https://doi.org/10.2337/db16-1452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Spracklen CN, Horikoshi M, Kim YJ, Lin K, Bragg F, Moon S, et al. Identification of type 2 diabetes loci in 433,540 East Asian individuals. Nature. 2020;582(7811):240–5. https://doi.org/10.1038/s41586-020-2263-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Beaumont RN, Warrington NM, Cavadino A, Tyrrell J, Nodzenski M, Horikoshi M, et al. Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics. Hum Mol Genet. 2018;27(4):742–56. https://doi.org/10.1093/hmg/ddx429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Karamitri A, Jockers R. Melatonin in type 2 diabetes mellitus and obesity. Nat Rev Endocrinol. 2019;15(2):105–25. https://doi.org/10.1038/s41574-018-0130-1.

    Article  CAS  PubMed  Google Scholar 

  62. Manchester LC, Coto-Montes A, Boga JA, Andersen LP, Zhou Z, Galano A, et al. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res. 2015;59(4):403–19. https://doi.org/10.1111/jpi.12267.

    Article  CAS  PubMed  Google Scholar 

  63. Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT. Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol. 2012;351(2):152–66. https://doi.org/10.1016/j.mce.2012.01.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bonnefond A, Clement N, Fawcett K, Yengo L, Vaillant E, Guillaume JL, et al. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat Genet. 2012;44(3):297–301. https://doi.org/10.1038/ng.1053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Scott RA, Lagou V, Welch RP, Wheeler E, Montasser ME, Luan J, et al. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat Genet. 2012;44(9):991–1005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Manning AK, Hivert MF, Scott RA, Grimsby JL, Bouatia-Naji N, Chen H, et al. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nat Genet. 2012;44(6):659–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet. 2010;42(2):105–16. https://doi.org/10.1038/ng.520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Prokopenko I, Poon W, Magi R, Prasad BR, Salehi SA, Almgren P, et al. A central role for GRB10 in regulation of islet function in man. PLoS Genet. 2014;10(4):e1004235. https://doi.org/10.1371/journal.pgen.1004235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Saxena R, Hivert MF, Langenberg C, Tanaka T, Pankow JS, Vollenweider P, et al. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet. 2010;42(2):142–8. https://doi.org/10.1038/ng.521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Walford GA, Gustafsson S, Rybin D, Stancakova A, Chen H, Liu CT, et al. Genome-wide association study of the modified Stumvoll insulin sensitivity index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci. Diabetes. 2016;65(10):3200–11. https://doi.org/10.2337/db16-0199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. •• Hayes MG, Urbanek M, Hivert MF, Armstrong LL, Morrison J, Guo C, et al. Identification of HKDC1 and BACE2 as genes influencing glycemic traits during pregnancy through genome-wide association studies. Diabetes. 2013;62(9):3282–91. https://doi.org/10.2337/db12-1692. This is the first GWAS to investigate genetic loci associated with glycemic traits during pregnancy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tan YX, Hu SM, You YP, Yang GL, Wang W. Replication of previous genome-wide association studies of HKDC1, BACE2, SLC16A11 and TMEM163 SNPs in a gestational diabetes mellitus case-control sample from Han Chinese population. Diabetes Metab Syndr Obes. 2019;12:983–9. https://doi.org/10.2147/DMSO.S207019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Moen GH, LeBlanc M, Sommer C, Prasad RB, Lekva T, Normann KR, et al. Genetic determinants of glucose levels in pregnancy: genetic risk scores analysis and GWAS in the Norwegian STORK cohort. Eur J Endocrinol. 2018;179(6):363–72. https://doi.org/10.1530/EJE-18-0478.

    Article  CAS  PubMed  Google Scholar 

  74. Guo C, Ludvik AE, Arlotto ME, Hayes MG, Armstrong LL, Scholtens DM, et al. Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1. Nat Commun. 2015;6:6069. https://doi.org/10.1038/ncomms7069.

    Article  CAS  PubMed  Google Scholar 

  75. Ludvik AE, Pusec CM, Priyadarshini M, Angueira AR, Guo C, Lo A, et al. HKDC1 is a novel hexokinase involved in whole-body glucose use. Endocrinology. 2016;157(9):3452–61. https://doi.org/10.1210/en.2016-1288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Khan MW, Priyadarshini M, Cordoba-Chacon J, Becker TC, Layden BT. Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice. Biochim Biophys Acta Mol basis Dis. 2019;1865(3):678–87. https://doi.org/10.1016/j.bbadis.2018.11.022.

    Article  CAS  PubMed  Google Scholar 

  77. Esterhazy D, Stutzer I, Wang H, Rechsteiner MP, Beauchamp J, Dobeli H, et al. Bace2 is a beta cell-enriched protease that regulates pancreatic beta cell function and mass. Cell Metab. 2011;14(3):365–77. https://doi.org/10.1016/j.cmet.2011.06.018.

    Article  CAS  PubMed  Google Scholar 

  78. Casas S, Casini P, Piquer S, Altirriba J, Soty M, Cadavez L, et al. BACE2 plays a role in the insulin receptor trafficking in pancreatic ss-cells. Am J Physiol Endocrinol Metab. 2010;299(6):E1087–95. https://doi.org/10.1152/ajpendo.00420.2010.

    Article  CAS  PubMed  Google Scholar 

  79. Alcarraz-Vizan G, Casini P, Cadavez L, Visa M, Montane J, Servitja JM, et al. Inhibition of BACE2 counteracts hIAPP-induced insulin secretory defects in pancreatic beta-cells. FASEB J. 2015;29(1):95–104. https://doi.org/10.1096/fj.14-255489.

    Article  CAS  PubMed  Google Scholar 

  80. •• Powe CE, Nodzenski M, Talbot O, Allard C, Briggs C, Leya MV, et al. Genetic determinants of glycemic traits and the risk of gestational diabetes mellitus. Diabetes. 2018;67(12):2703–9. https://doi.org/10.2337/db18-0203. This study shows that polygenic score consisted of variants associated with glycemic traits outside of pregnancy and T2D is associated with glycemic traits in pregnancy and risk of GDM.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Sullivan SD, Jablonski KA, Florez JC, Dabelea D, Franks PW, Dagogo-Jack S, et al. Genetic risk of progression to type 2 diabetes and response to intensive lifestyle or metformin in prediabetic women with and without a history of gestational diabetes mellitus. Diabetes Care. 2014;37(4):909–11. https://doi.org/10.2337/dc13-0700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Cormier H, Vigneault J, Garneau V, Tchernof A, Vohl MC, Weisnagel SJ, et al. An explained variance-based genetic risk score associated with gestational diabetes antecedent and with progression to pre-diabetes and type 2 diabetes: a cohort study. BJOG. 2015;122(3):411–9. https://doi.org/10.1111/1471-0528.12937.

    Article  CAS  PubMed  Google Scholar 

  83. Ekelund M, Shaat N, Almgren P, Anderberg E, Landin-Olsson M, Lyssenko V, et al. Genetic prediction of postpartum diabetes in women with gestational diabetes mellitus. Diabetes Res Clin Pract. 2012;97(3):394–8. https://doi.org/10.1016/j.diabres.2012.04.020.

    Article  CAS  PubMed  Google Scholar 

  84. Kwak SH, Choi SH, Kim K, Jung HS, Cho YM, Lim S, et al. Prediction of type 2 diabetes in women with a history of gestational diabetes using a genetic risk score. Diabetologia. 2013;56(12):2556–63. https://doi.org/10.1007/s00125-013-3059-x.

    Article  PubMed  Google Scholar 

  85. Li M, Rahman ML, Wu J, Ding M, Chavarro JE, Lin Y, et al. Genetic factors and risk of type 2 diabetes among women with a history of gestational diabetes: findings from two independent populations. BMJ Open Diabetes Res Care. 2020;8(1). https://doi.org/10.1136/bmjdrc-2019-000850.

  86. Udler MS, McCarthy MI, Florez JC, Mahajan A. Genetic risk scores for diabetes diagnosis and precision medicine. Endocr Rev. 2019;40(6):1500–20. https://doi.org/10.1210/er.2019-00088.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Khera AV, Kathiresan S. Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet. 2017;18(6):331–44. https://doi.org/10.1038/nrg.2016.160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Khera AV, Chaffin M, Wade KH, Zahid S, Brancale J, Xia R, et al. Polygenic prediction of weight and obesity trajectories from birth to adulthood. Cell. 2019;177(3):587–96 e9. https://doi.org/10.1016/j.cell.2019.03.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26(17):2190–1. https://doi.org/10.1093/bioinformatics/btq340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Cho YS, Chen CH, Hu C, Long J, Ong RT, Sim X, et al. Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in East Asians. Nat Genet. 2011;44(1):67–72. https://doi.org/10.1038/ng.1019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI15C3131) to S.H.K. C.E.P. is supported by NIH K23DK113218 and the Robert Wood Johnson Foundation’s Harold Amos Medical Faculty Development Program.

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Authors and Affiliations

  1. Diabetes Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA, USA

    Camille E. Powe

  2. Harvard Medical School, Boston, MA, USA

    Camille E. Powe

  3. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Camille E. Powe & Soo Heon Kwak

  4. Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea

    Soo Heon Kwak

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  1. Camille E. Powe
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Correspondence to Soo Heon Kwak.

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Powe, C.E., Kwak, S.H. Genetic Studies of Gestational Diabetes and Glucose Metabolism in Pregnancy. Curr Diab Rep 20, 69 (2020). https://doi.org/10.1007/s11892-020-01355-3

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