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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

Number Gene Full name Locus Pathophysiology
1 TCF7L2 Transcription factor 7-like 2 10q2 Increases apoptosis, impairing insulin secretion [19].
2 KCNQ1 Potassium voltage-gated channel subfamily Q member 1 11p15.5-15.4 It disrupts the influx of calcium into the channel, resulting in decreased insulin secretion [20].
3 CENTD2/ARAP1 Centaurin-delta-2/ ArfGAP with rhoGAP domain, ankyrin repeat and PH domain 1 11q13.4 Causes disruption of glucose-induced insulin secretion [21].
4 MTNR1B Melatonin receptor 1B 11q14.3 Decreases insulin secretion, elevating fasting glucose levels [22].
5 IGF1 Insulin-like growth factor 1 12q23.2 Induces high body mass (HBM), leading to metabolic disturbances, especially insulin resistance and hyperinsulinemia [23].
6 IGF2 Insulin-like growth factor 2 11p15.5 Overexpression of IGF2 leads to β-cell dedifferentiation and endoplasmic reticulum stress, causing islet dysfunction [24].
7 IGFBP-1 Insulin like growth factor binding protein 1 7p12.3 Decreased blood levels of IGFBP-1 cause overexpression of IGF-I, resulting in inflammation [25].
8 IGFBP-2 Insulin like growth factor binding protein 3 2q35 Reduced expression of IGFBP-2 inhibits adipogenesis, leading to obesity and insulin resistance [26].
9 IGF2BP2 Insulin like growth factor 2 mRNA binding protein 2 3q27.2 Impairs β-cell function and modulates obesity, altering insulin sensitivity [27].
10 IGFBP-3 Insulin like growth factor binding protein 3 7p12.3 Overexpression of IGFBP-3 predisposes to HBM body, disrupting glucose metabolism [28].
11 IGFBP-4 Insulin like growth factor binding protein 4 17q21.2 Reduced levels cause HBM and insulin resistance [28].
12 IGFBP5 Insulin like growth factor binding protein 5 2q35 Disrupts IGF-1 signaling pathway, leading to insulin insensitivity [29].
13 PPARG Peroxisome proliferator-activated receptor gamma 3p25.2 Stimulates abnormal fat deposition in tissues, causing obesity and insulin resistance [27].
14 KCNJ11 Potassium voltage-gated channel subfamily J member 11 11p15.1 Reduces the sensitivity of pancreatic beta-cell KATP channel subunit (Kir6.2), resulting in decreased insulin release [28].
15 INSR Insulin receptor 19p13.2 Predisposes to obesity, leading to insulin resistance [29].
16 ADRB2 Adrenoceptor beta 2 5q32 Increases 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].
17 ADRB3 Adrenoceptor beta 3 8p11.23 Increases body weight, predisposing to obesity and insulin resistance [31].
18 GNB3 G protein subunit beta 3 12p13.31 Causes high-fat deposition and obesity [32].
19 ABCC8 ATP binding cassette subfamily c member 8 11p15.1 Loss of function of the gene disrupts the KATP channel function, increasing the body weight and causing hyperinsulinism [33].
20 CAPN10 Malpain 10 2q37.3 Increases body mass, initiating insulin resistance [34].
21 MBL2 Mannose-binding lectin 10q21.1 Causes frequent infections and chronic inflammatory diseases, leading to high-fat deposition and insulin resistance [35].
22 GLUT4/SLC2A4 Glucose transporter type 4/Solute carrier family 2 member 4 17p13.1 Impairs insulin signaling pathway [36].
23 RBP4 Retinol binding protein-4 10q23.33 Increases gluconeogenesis and impairs insulin signaling in muscles [37].
24 PCK1 Phosphoenolpyruvate carboxykinase 1 20q13.31 Induces high levels of fasting insulin, causing abnormal glucose metabolism [38].
25 PIK3R1/ PI3K Phosphoinositide-3-kinase regulatory subunit 1 5q13.1 Disrupts insulin signaling pathway in skeletal muscle and inhibit liver gluconeogenesis [38].
26 STRA6 Signaling receptor and transporter of retinol STRA6 15q24.1 Promotes fat deposition, predisposing to obesity and insulin resistance [39].
27 VDR Vitamin D receptor 12q13 Predisposes to obesity, causing metabolic disorder, especially insulin resistance [40, 41].
28 CDKAL1 Cyclin-dependent Kinase 5 Regulatory subunit-associated protein 1-like 1 6p22.3 Inhibits the conversion of proinsulin to insulin through protein translation, leading to insulin resistance [42].
29 GCK Glucokinase 7p13 Increases body fat mass, resulting in insulin resistance [43].
30 CDKN2A/2B Cyclin-dependent kinase inhibitor 2a 9p21.3 Affects proinsulin conversion to insulin and reduces insulin sensitivity [44].
31 SRR Serine racemase 17p13.3 Disrupts the secretion of insulin and/or glucagon [45].
32 HHEX/IDE Hematopoietically expressed homeobox 10q23.33 Causes pancreatic and liver developmental error [46].
33 SLC30A8 Solute carrier family 30 member 8 8q24.11 Modulates loss of zinc in the beta cells, destabilizing insulin molecule s[47].
34 LEP Leptin 7q31.3 Promotes inflammation, causing energy imbalance and obesity [48].
35 LEPR leptin receptor 1p31 Induces high-fat mass and insulin resistance [49].
36 HNF1B/TCF2 Hepatocyte nuclear factor 1B 17q12 Causes β-cell dysfunction [50, 51].
37 TNF-α/TNF Tumor necrosis factor-α 6p21.33 Causes inflammatory and oxidative stress [52]).
38 HNF4A/TCF1 Hepatocyte nuclear factor 4 alpha 20q12 Induces β-cell dysfunction [50, 51].
39 WFS1 Wolfram syndrome 1 4p16.1 Initiates endoplasmic reticulum stress and mitochondrial disorder, leading to β-cell dysfunction [53].
40 IRS1 insulin receptor substrate 1 2q36.3 Induces an inflammatory response and causing low insulin sensitivity [54].
41 HTR2B/ 5-HT-1A 5-hydroxytryptamine receptor 1a 5q12.3 Reduces beta-cell proliferation and increases body weight [55].
42 TPH1 Tryptophan hydroxylase 1 11p15.1 Causes low levels of serotonin, increasing weight gain and causing insulin intolerance [56].
43 5-HT1A/HTR3A 5-hydroxytryptamine receptor 1a 5q12.3 Causes low serotonin levels, resulting in insulin resistance [57].
44 HNF1A Hepatocyte nuclear factor-1 alpha 12q24.31 Causes adiposity, leading to pre-pregnancy obesity and insulin resistance [57].
45 GCKR Glucokinase regulator 2p23.3 Overexpression of GCKR causes hyperactivity of GCK, reducing glucose and increasing fat accumulation [58]. Loss of the function reduces GCK expression, impairing glucose clearance [59].
46 MIF Macrophage migration inhibitory factor 22q11.23 Overexpression of the MIF gene in placental tissue causes insulin resistance [60].
47 ADRA2A Alpha-2-adrenergic receptors 10q25.2 Increases body fat mass, leading to loss of glucose regulation [61].
48 SLC6A4 Solute carrier family 6 member 4 17q11.2 Impairs serotonin metabolism, increasing body weight and causing insulin resistance [62].
49 FTO Fat mass and obesity-associated gene/Alpha-ketoglutarate dependent dioxygenase 16q12.2 Causes adiposity, leading to pre-pregnancy obesity and insulin resistance [63].
50 TLE1 Transducin-like enhancer of split-1 9q21.32 Elevates fasting glucose level and reduces insulin secretion [64].
51 ADCY5 Adenylate cyclase 5 3q21.1 Alters ADCY5 expression in pancreatic beta cells, impairing glucose signaling [65].
52 IL-1β Interleukin-1 beta 2q14.1 Impairs pancreatic β-cells, decreasing insulin secretion [66].
53 IL-6 Interleukin-6 7p15.3 Overexpression destroys pancreatic β-cells, resulting in apoptosis and low insulin synthesis [67].
54 IL-10 Interleukin-10 1q32.1 Overexpression compromises immune response, disrupting insulin metabolism [68].
55 PAX8 Paired box 8 2q14.1 Reduces islet viability and beta cell survival [69].
56 ADIPOQ (diponectin gene) Adiponectin, C1Q and collagen domain containing 3q27.3 Causes low adiponectin, leading to obesity and insulin resistance [70].
57 RARRES2 (Chemerin gene) retinoic acid receptor responder 2 7q36.1 Initiates inflammation and energy imbalance, leading to obesity and insulin resistance [71].
58 SERPINA12 (Vaspin gene) Serpin family a member 12 14q32.13 Causes inflammation, loss of energy balance, and obesity [72].
59 RETN Resistin 19p13.2 Causes a loss of energy balance, obesity, and insulin resistance [73].
60 APLN Apelin Xq26.1 Causes a loss of energy balance, obesity, and insulin resistance [74].
61 NUCB2 (nesfatin 1 gene) Nucleobindin 2 11p15.1 Causes a loss of energy balance, obesity, and insulin resistance [75].
62 ITLN1 Intelectin-1/Omentin-1 1q23.3 Loss of function induces insulin resistance [76].
63 NAMPT/PBEF1 (Visfatin gene) Nicotinamide phosphoribosyltransferase 7q22.3 Causes obesity and insulin resistance [76].
64 HMG20A/ iBRAF High mobility group protein 20a 15q24.3 Depletion 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].
65 RREB1 Ras responsive element binding protein 1 6p24.3 Causes fat deposition and beta cell dysfunction [78].
66 GLIS3 GLIS family zinc finger 3 9p24.2 Causes fat deposition and beta cell dysfunction [78].
67 GPSM1 G protein signaling modulator 1 9q34.3 Causes fat deposition and beta cell dysfunction [78].
68 mtDNA Mitochondrial DNA All cells Induces oxidative stress and mitochondrial disorder, causing insulin resistance [79].
69 PRLR Prolactin receptor 5p13.2 Modulates loss of PRLR signaling in β-cells. reducing β-cell proliferation and expansion during pregnancy [80].
70 MAFB MAF bZIP transcription factor B 20q12 Causes inadequate β-cell expansion [80].
71 SERT Serotonin transporter 17q11.1-12 Stimulates abnormal fat accumulation in both white and brown adipose tissues, causing glucose intolerance and insulin resistance [81].
72 PAI-1 Plasminogen activator inhibitor 1 7q22 Predisposes to adiposity, increasing body weight and affecting pancreatic beta-cell function [82].
73 TSPAN8 Tetraspanin-8 12q21.1 Impairs gestational glucose tolerance [83].
74 G6PC2 Glucose-6-phosphatase catalytic subunit 2 2q31.1 Elevates fasting glucose level and reduces insulin secretion [64].
75 PTPRD Protein tyrosine phosphatase receptor type d 9p24.1-p23 Disrupts insulin signaling pathway, leading to altered insulin sensitivity and glucose homeostasis [84].
76 CRP C-reactive protein 1q23.2 Overexpression causes obesity, resulting in systemic inflammation and insulin resistance [85].
77 GK Glycerol kinase Xp21.2 Deficiency causes abnormal insulin metabolism [86].
78 PAX4 Paired box gene 4 7q32.1 Impairs fetal islet cell differentiation, altering insulin sensitivity later in life [87].
79 HDAC4 Histone deacetylase 4 2q37.3 Causes β-cell loss, leading to decreased insulin secretion. Also represses beta-cell transcriptional factors [88].
80 FETUA/ AHSG Fetuin-a 3q27.3 Increases body mass, insulin secretion and C-peptide levels, but lower insulin sensitivity [89].
81 FETUB Fetuin-b 3q27.3 Increases hepatic steatosis, impairing insulin secretion and glucose metabolism [90].
82 FGF21 Fibroblast growth factor 21 10q26.13 Cause an abnormal glucose metabolism independent of insulin resistance [91].
83 SNORA8    An emerging candidate gene [92]