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Table 1 GDM predisposing genes showing locations and phathophysiology

From: Update on the genetic and epigenetic etiology of gestational diabetes mellitus: a review

NumberGeneFull nameLocusPathophysiology
1TCF7L2Transcription factor 7-like 210q2Increases apoptosis, impairing insulin secretion [19].
2KCNQ1Potassium voltage-gated channel subfamily Q member 111p15.5-15.4It disrupts the influx of calcium into the channel, resulting in decreased insulin secretion [20].
3CENTD2/ARAP1Centaurin-delta-2/ ArfGAP with rhoGAP domain, ankyrin repeat and PH domain 111q13.4Causes disruption of glucose-induced insulin secretion [21].
4MTNR1BMelatonin receptor 1B11q14.3Decreases insulin secretion, elevating fasting glucose levels [22].
5IGF1Insulin-like growth factor 112q23.2Induces high body mass (HBM), leading to metabolic disturbances, especially insulin resistance and hyperinsulinemia [23].
6IGF2Insulin-like growth factor 211p15.5Overexpression of IGF2 leads to β-cell dedifferentiation and endoplasmic reticulum stress, causing islet dysfunction [24].
7IGFBP-1Insulin like growth factor binding protein 17p12.3Decreased blood levels of IGFBP-1 cause overexpression of IGF-I, resulting in inflammation [25].
8IGFBP-2Insulin like growth factor binding protein 32q35Reduced expression of IGFBP-2 inhibits adipogenesis, leading to obesity and insulin resistance [26].
9IGF2BP2Insulin like growth factor 2 mRNA binding protein 23q27.2Impairs β-cell function and modulates obesity, altering insulin sensitivity [27].
10IGFBP-3Insulin like growth factor binding protein 37p12.3Overexpression of IGFBP-3 predisposes to HBM body, disrupting glucose metabolism [28].
11IGFBP-4Insulin like growth factor binding protein 417q21.2Reduced levels cause HBM and insulin resistance [28].
12IGFBP5Insulin like growth factor binding protein 52q35Disrupts IGF-1 signaling pathway, leading to insulin insensitivity [29].
13PPARGPeroxisome proliferator-activated receptor gamma3p25.2Stimulates abnormal fat deposition in tissues, causing obesity and insulin resistance [27].
14KCNJ11Potassium voltage-gated channel subfamily J member 1111p15.1Reduces the sensitivity of pancreatic beta-cell KATP channel subunit (Kir6.2), resulting in decreased insulin release [28].
15INSRInsulin receptor19p13.2Predisposes to obesity, leading to insulin resistance [29].
16ADRB2Adrenoceptor beta 25q32Increases the secretion of vascular endothelial growth Factor-A (VEGF-A) in the β-cells, resulting in hyper-vascularized islets and disrupting insulin secretion and glucose metabolism [30].
17ADRB3Adrenoceptor beta 38p11.23Increases body weight, predisposing to obesity and insulin resistance [31].
18GNB3G protein subunit beta 312p13.31Causes high-fat deposition and obesity [32].
19ABCC8ATP binding cassette subfamily c member 811p15.1Loss of function of the gene disrupts the KATP channel function, increasing the body weight and causing hyperinsulinism [33].
20CAPN10Malpain 102q37.3Increases body mass, initiating insulin resistance [34].
21MBL2Mannose-binding lectin10q21.1Causes frequent infections and chronic inflammatory diseases, leading to high-fat deposition and insulin resistance [35].
22GLUT4/SLC2A4Glucose transporter type 4/Solute carrier family 2 member 417p13.1Impairs insulin signaling pathway [36].
23RBP4Retinol binding protein-410q23.33Increases gluconeogenesis and impairs insulin signaling in muscles [37].
24PCK1Phosphoenolpyruvate carboxykinase 120q13.31Induces high levels of fasting insulin, causing abnormal glucose metabolism [38].
25PIK3R1/ PI3KPhosphoinositide-3-kinase regulatory subunit 15q13.1Disrupts insulin signaling pathway in skeletal muscle and inhibit liver gluconeogenesis [38].
26STRA6Signaling receptor and transporter of retinol STRA615q24.1Promotes fat deposition, predisposing to obesity and insulin resistance [39].
27VDRVitamin D receptor12q13Predisposes to obesity, causing metabolic disorder, especially insulin resistance [40, 41].
28CDKAL1Cyclin-dependent Kinase 5 Regulatory subunit-associated protein 1-like 16p22.3Inhibits the conversion of proinsulin to insulin through protein translation, leading to insulin resistance [42].
29GCKGlucokinase7p13Increases body fat mass, resulting in insulin resistance [43].
30CDKN2A/2BCyclin-dependent kinase inhibitor 2a9p21.3Affects proinsulin conversion to insulin and reduces insulin sensitivity [44].
31SRRSerine racemase17p13.3Disrupts the secretion of insulin and/or glucagon [45].
32HHEX/IDEHematopoietically expressed homeobox10q23.33Causes pancreatic and liver developmental error [46].
33SLC30A8Solute carrier family 30 member 88q24.11Modulates loss of zinc in the beta cells, destabilizing insulin molecule s[47].
34LEPLeptin7q31.3Promotes inflammation, causing energy imbalance and obesity [48].
35LEPRleptin receptor1p31Induces high-fat mass and insulin resistance [49].
36HNF1B/TCF2Hepatocyte nuclear factor 1B17q12Causes β-cell dysfunction [50, 51].
37TNF-α/TNFTumor necrosis factor-α6p21.33Causes inflammatory and oxidative stress [52]).
38HNF4A/TCF1Hepatocyte nuclear factor 4 alpha20q12Induces β-cell dysfunction [50, 51].
39WFS1Wolfram syndrome 14p16.1Initiates endoplasmic reticulum stress and mitochondrial disorder, leading to β-cell dysfunction [53].
40IRS1insulin receptor substrate 12q36.3Induces an inflammatory response and causing low insulin sensitivity [54].
41HTR2B/ 5-HT-1A5-hydroxytryptamine receptor 1a5q12.3Reduces beta-cell proliferation and increases body weight [55].
42TPH1Tryptophan hydroxylase 111p15.1Causes low levels of serotonin, increasing weight gain and causing insulin intolerance [56].
435-HT1A/HTR3A5-hydroxytryptamine receptor 1a5q12.3Causes low serotonin levels, resulting in insulin resistance [57].
44HNF1AHepatocyte nuclear factor-1 alpha12q24.31Causes adiposity, leading to pre-pregnancy obesity and insulin resistance [57].
45GCKRGlucokinase regulator2p23.3Overexpression of GCKR causes hyperactivity of GCK, reducing glucose and increasing fat accumulation [58]. Loss of the function reduces GCK expression, impairing glucose clearance [59].
46MIFMacrophage migration inhibitory factor22q11.23Overexpression of the MIF gene in placental tissue causes insulin resistance [60].
47ADRA2AAlpha-2-adrenergic receptors10q25.2Increases body fat mass, leading to loss of glucose regulation [61].
48SLC6A4Solute carrier family 6 member 417q11.2Impairs serotonin metabolism, increasing body weight and causing insulin resistance [62].
49FTOFat mass and obesity-associated gene/Alpha-ketoglutarate dependent dioxygenase16q12.2Causes adiposity, leading to pre-pregnancy obesity and insulin resistance [63].
50TLE1Transducin-like enhancer of split-19q21.32Elevates fasting glucose level and reduces insulin secretion [64].
51ADCY5Adenylate cyclase 53q21.1Alters ADCY5 expression in pancreatic beta cells, impairing glucose signaling [65].
52IL-1βInterleukin-1 beta2q14.1Impairs pancreatic β-cells, decreasing insulin secretion [66].
53IL-6Interleukin-67p15.3Overexpression destroys pancreatic β-cells, resulting in apoptosis and low insulin synthesis [67].
54IL-10Interleukin-101q32.1Overexpression compromises immune response, disrupting insulin metabolism [68].
55PAX8Paired box 82q14.1Reduces islet viability and beta cell survival [69].
56ADIPOQ (diponectin gene)Adiponectin, C1Q and collagen domain containing3q27.3Causes low adiponectin, leading to obesity and insulin resistance [70].
57RARRES2 (Chemerin gene)retinoic acid receptor responder 27q36.1Initiates inflammation and energy imbalance, leading to obesity and insulin resistance [71].
58SERPINA12 (Vaspin gene)Serpin family a member 1214q32.13Causes inflammation, loss of energy balance, and obesity [72].
59RETNResistin19p13.2Causes a loss of energy balance, obesity, and insulin resistance [73].
60APLNApelinXq26.1Causes a loss of energy balance, obesity, and insulin resistance [74].
61NUCB2 (nesfatin 1 gene)Nucleobindin 211p15.1Causes a loss of energy balance, obesity, and insulin resistance [75].
62ITLN1Intelectin-1/Omentin-11q23.3Loss of function induces insulin resistance [76].
63NAMPT/PBEF1 (Visfatin gene)Nicotinamide phosphoribosyltransferase7q22.3Causes obesity and insulin resistance [76].
64HMG20A/ iBRAFHigh mobility group protein 20a15q24.3Depletion represses expression of insulin-producing genes such as NeuroD, Mafa and GCK, and enhances beta-cell de-differentiating gene such as PAX4 and REST [77].
65RREB1Ras responsive element binding protein 16p24.3Causes fat deposition and beta cell dysfunction [78].
66GLIS3GLIS family zinc finger 39p24.2Causes fat deposition and beta cell dysfunction [78].
67GPSM1G protein signaling modulator 19q34.3Causes fat deposition and beta cell dysfunction [78].
68mtDNAMitochondrial DNAAll cellsInduces oxidative stress and mitochondrial disorder, causing insulin resistance [79].
69PRLRProlactin receptor5p13.2Modulates loss of PRLR signaling in β-cells. reducing β-cell proliferation and expansion during pregnancy [80].
70MAFBMAF bZIP transcription factor B20q12Causes inadequate β-cell expansion [80].
71SERTSerotonin transporter17q11.1-12Stimulates abnormal fat accumulation in both white and brown adipose tissues, causing glucose intolerance and insulin resistance [81].
72PAI-1Plasminogen activator inhibitor 17q22Predisposes to adiposity, increasing body weight and affecting pancreatic beta-cell function [82].
73TSPAN8Tetraspanin-812q21.1Impairs gestational glucose tolerance [83].
74G6PC2Glucose-6-phosphatase catalytic subunit 22q31.1Elevates fasting glucose level and reduces insulin secretion [64].
75PTPRDProtein tyrosine phosphatase receptor type d9p24.1-p23Disrupts insulin signaling pathway, leading to altered insulin sensitivity and glucose homeostasis [84].
76CRPC-reactive protein1q23.2Overexpression causes obesity, resulting in systemic inflammation and insulin resistance [85].
77GKGlycerol kinaseXp21.2Deficiency causes abnormal insulin metabolism [86].
78PAX4Paired box gene 47q32.1Impairs fetal islet cell differentiation, altering insulin sensitivity later in life [87].
79HDAC4Histone deacetylase 42q37.3Causes β-cell loss, leading to decreased insulin secretion. Also represses beta-cell transcriptional factors [88].
80FETUA/ AHSGFetuin-a3q27.3Increases body mass, insulin secretion and C-peptide levels, but lower insulin sensitivity [89].
81FETUBFetuin-b3q27.3Increases hepatic steatosis, impairing insulin secretion and glucose metabolism [90].
82FGF21Fibroblast growth factor 2110q26.13Cause an abnormal glucose metabolism independent of insulin resistance [91].
83SNORA8  An emerging candidate gene [92]