Genetic and Epigenetic Alterations in Gestational Diabetes

Year 2018, Volume: 2 Issue: 1, 9 - 15, 01.04.2018

Sevim Karakaş Çelik Ayşe Sebla Yamak

Abstract

Gestational Diabetes is glucose intolerance that are diagnosed or started for the first time in pregnancy. In pregnancies diagnosed with

gestational diabetes mellitus, complication rates increase in mother and newborn. Many risk factors have been identified for GDM.

These include anemia, advanced maternal age, high parity, GDM in previous gestation, or premature birth of macrosomic baby, short

stature, obesity, multiple gestation, high blood pressure during pregnancy and family history of diabetes. The prevalence of GDM varies

between different populations, with prevalence ranging from 7% to 17% in different populations. There is important role of genetic and

epigenetic differences in variability of GDM prevalence between populations.

Most of the genetic studies on GDM focus on biologically plausible candidate gene analyzes. Two different meta-analyzes involving a

majority of these studies were performed, and these meta-analyzes revealed 8 genes associated with GDM. These genes are; TCF7L2,

GCK, KCNJ11, KCNQ1, CDKAL1, IGF2BP2, MTNR1B and IRS1. All of these locations are also related to the T2DM risk. The majority

of these genes, including GCK, KCNJ11, KCNQ1, MTNR1B, IGF2BP2, CDKAL1 and TCF7L2, encode proteins that are important for

beta cell function or development. There is also evidence that epigenetic factors play an important role in the pathogenesis of GDM. In

this article, genetic and epigenetic factors thought to play a role in the pathogenesis of GDM are presented.

Keywords

Gestational diabetes, Genetics, Epigenetics

Gestasyonel Diyabette Genetik ve Epigenetik Değişimler

Abstract

Gestasyonel Diyabet (GDM) ilk defa gebelikte teşhis edilen veya başlayan farklı derecelerdeki glukoz intöleransıdır. GDM tanısı alan
gebelerde ve yeni doğanda komplikasyon oranı artar. GDM için birçok risk faktörü tespit edilmiş olup bunlar ileri anne yaşı, yüksek
parite, önceki gebelikte GDM öyküsü, ya da makrozomik bebeğin erken doğumu, kısa boy, obezite, çoklu gebelik, gebelik sırasında
yüksek kan basıncı ve ailede diyabet öyküsüdür. GDM prevelansı farklı populasyonlar arasında değişkenlik göstermekte olup bu değer
% 7 ile % 17 arasında değişir. GDM sıklığının populasyonlar arasında değişkenlik göstermesinde, genetik ve epigenetik farklılıkların
önemli rolü olduğu düşünülmektedir.
GDM ile ilgili yapılan genetik çalışmaların çoğu biyolojik olarak makul olan aday gen analizlerine dayanmaktadır. Bu çalışmaların
birçoğunu içeren iki farklı meta-analiz gerçekleştirilmiş olup bu iki meta-analiz sonucunda GDM ile ilişki gösteren 8 gen tespit edilmiştir.
Bu genler; TCF7L2, GCK, KCNJ11, KCNQ1, CDKAL1, IGF2BP2, MTNR1B ve IRS1’dir. Bu lokusların/genlerin tümü aynı zamanda
Tip 2 Diyabet (T2DM) riski ile de ilişkilidir. GCK, KCNJ11, KCNQ1, MTNR1B, IGF2BP2, CDKAL1 ve TCF7L2’nin de dahil olduğu
bu genlerin çoğunluğu, beta hücre fonksiyonu veya gelişimi için önemli olan proteinleri kodlamaktadır. Bunun yanı sıra epigenetik
faktörlerin de GDM patogenezinde oldukça önemli rol oynadığını gösteren kanıtlar mevcuttur. Bu makalede GDM patogenezinde rolü
olduğu düşünülen genetik ve epigenetik faktörler sunulmuştur.

Keywords

Gestasyonel diyabet, Genetik, Epigenetik

References

• 1. Löbner K, et al. Predictors of postpartum diabetes in women with gestational diabetes mellitus. Diabetes. 2006;55(3):792- 797.
• 2. Ashwal E, Hod M. Gestational diabetes mellitus: Where are we now? Clin Chim Acta. 2015; 451:14-20.
• 3. Buchanan TA, et al. What is gestational diabetes? Diabetes Care. 2007;30:105–111.
• 4. Buchanan TA, et al. Gestational diabetes mellitus:risks and management during and after pregnancy. Nat Rev Endocrinol. 2012;8:639–649.
• 5. Dabelea D, et al. Kaiser Permanente of Colorado GDMSP, increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM screening program. Diabetes Care. 2005;28:579–584.
• 6. Ferrara A, et al. An increase in the incidence of gestational diabetes mellitus: Northern California, 1991-2000. Obstet Gynecol. 2004;103:526–533.
• 7. Butler AE, et al. Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia. 2010;53: 2167–2176.
• 8. Lain KY, Catalano PM. Metabolic changes in pregnancy. Clin Obstet Gynecol. 2007;50:938–948.
• 9. Bajaj K, Gross SJ. The genetics of diabetic pregnancy. Best Pract Res Clin Obstet Gynaecol. 2015;29(1):102-109.
• 10. Genetics and Health. World Health Organization. (http://www. who.int/rpc/genomics_report.pdf. Accessed Date 19.10.2017)
• 11. Williams MA, et al. Familial aggregation of Type 2 diabetes and chronic hypertension in women with gestational diabetes mellitus. J Reprod Med. 2003;48(12):955e62.
• 12. Practice Bulletin No. 137. Gestational diabetes mellitus. Obstet Gynecol. 2013;122(2 Pt 1): 406-416.
• 13. Galtier F. Definition, epidemiology, risk factors. Diabetes Metab. 2010;36(6 Pt 2):628-651.
• 14. Lowe WL Jr, et al. Gestational diabetes mellitus, programing and epigenetics, Jie Yan and Huixia Yang. Curr Diab Rep. 2016;16(2):15.
• 15. Korte A, Farlow A. The advantages and limitations of trait analysis with GWAS: A review. Plant Methods. 2013;9(1):29.
• 16. Mao H, et al. Meta-analysis of the relationship between common type 2 diabetes risk gene variants with gestational diabetes mellitus. PLoS One. 2012;7:e45882.
• 17. Zhang C, et al. Genetic variants and the risk of gestational diabetes mellitus: A systematic review. Hum Reprod Update. 2013;19:376–390.
• 18. Morris AP, et al. Diabetes Genetics Replication and Metaanalysis (DIAGRAM) Consortium. Large-scaleassociationanalysisprovidesinsightsintothegeneticarchitectureandpathophysiology of type 2 diabetes. NatGenet. 2012;44:981–990.
• 19. Basile KJ, et al. Genetic susceptibility to type 2 diabetes and obesity: Follow-up of findings from genomewide association studies. Int J Endocrinol. 2014;2014:769671.
• 20. Mohlke KL, Boehnke M. Recent advances in understanding the genetic architecture of type 2 diabetes. Hum Mol Genet. 2015;24: R85–92.
• 21. Dimas AS, et al. Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. Diabetes. 2014;63:2158–2171.
• 22. Kurokawa N, et al. The ADRB3 Trp64Arg variant and BMI: A meta-analysis of 44 833 individuals. Int J Obes (Lond). 2008;32:1240–1249.
• 23. Stuebe AM, et al. Maternal genotype and gestational diabetes. Am J Perinatol. 2014;31:69–76.
• 24. IrwinDM, Tan H. Evolution of glucose utilization: Glucokinase and glucokinase regulator protein. Mol Phylogenet Evol. 2014;70:195–203.
• 25. Huopio H, et al. Association of risk variants for type 2 diabetes and hyperglycemia with gestational diabetes. Eur J Endocrinol. 2013;169:291–297.
• 26. Huerta-Chagoya A, et al. Genetic determinants for gestational diabetes mellitus and related metabolic traits in Mexican women. PLoS One. 2015;10:e0126408.
• 27. Grant SF, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006;38(3):320e3.
• 28. Florez JC, et al. Diabetes Prevention Program Research Group. TCF7L2 polymorphisms and progression to diabetes in the diabetes prevention program. N Engl J Med. 2006;355(3):241- 250.
• 29. Kang S, et al. Association of the rs7903146 polymorphism in transcription factor 7-like 2 (TCF7L2) gene with gestational diabetes mellitus: A meta-analysis. Gynecol Endocrinol. 2013;29(10):873e7.
• 30. Li Q, et al. KCNJ11 E23K variant is associated with the therapeutic effect of sulphonylureas in Chinese type 2 diabetic patients. Clin Exp Pharmacol Physiol. 2014;41:748–754.
• 31. Maruthur NM, et al.The pharmacogenetics of type 2 diabetes: A systematic review. Diabetes Care. 2014;37:876–886.
• 32. Desoye G, Hauguel-de Mouzon S. The human placenta in gestational diabetesmellitus. The insulin and cytokine network. Diabetes Care. 2007;30(2):120–126.
• 33. Newbern D, Freemark M. Placental hormones and the control of maternal metabolism and fetal growth. Curr Opin Endocrinol Diabet Obes. 2011;18:409–416.
• 34. Lowe LP, et al. Inflammatory mediators and glucose in pregnancy: Results from a subset of the hyperglycemia and adverse pregnancy outcome (HAPO) study. J Clin Endocrinol Metab. 2010;95: 5427–5434.
• 35. Urbanek M, et al. The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy. PLoS One. 2012;7:e32958.
• 36. Guzmán-Flores JM, et al. Association analysis between -308G/ A and -238G/A TNF-alpha gene promoter polymorphisms and insulin resistance in Mexican women with gestational diabetes mellitus. J Investig Med. 2013;61:265–269.
• 37. Kwak SH, et al. A genome-wide association study of gestational diabetes mellitus in Korean women. Diabetes. 2012;61:531– 541.
• 38. Yan J, Yang H. Gestational diabetes mellitus, programing and epigenetics. J Matern Fetal Neonatal Med. 2014;27(12):1266- 1269.
• 39. Ling C, et al. Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insülin secretion. Diabetologia. 2008;51:615–622.
• 40. Park JH, et al. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest. 2008;118:2316–2324.
• 41. Baker J, et al. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993;75:73–82.
• 42. Tobi EW, et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet. 2009;18:4046–4053.
• 43. Painter RC, et al. Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life. BJOG. 2008;115:1243–1249.
• 44. Simmons RA, et al. Intrauterine growth retardation leads to the development of type 2 diabetes in the rat. Diabetes. 2001;50:2279–2286.
• 45. Ng SF, et al. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature. 2010;467:963–966.
• 46. Zhao C, et al. Early second-trimester serum MiRNA profiling predicts gestational diabetes mellitus. PLoS ONE. 2011;6(8):e23925.
• 47. Collares CV, et al. Identifying common and specific microRNAs expressed in peripheral blood mononuclear cell of type 1, type 2, and gestational diabetes mellitus patients. BMC Res Notes. 2013;6:491.
• 48. Pillar N, et al. The possible involvement of microRNAs in preeclampsia and gestational diabetes mellitus. Best Pract Res Clin Obstet Gynaecol. 2015;29(2):176-182.