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 | |
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 | |
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 | Â | Â | An emerging candidate gene [92] |