Update on the genetic and epigenetic etiology of gestational diabetes mellitus: a review
Tajudeen Yahaya, Titilola Salisu, Yusuf Abdulrahman, Abdulrazak Umar
RR E V I E W Open Access
Update on the genetic and epigeneticetiology of gestational diabetes mellitus: areview
Tajudeen O. Yahaya , Titilola Salisu , Yusuf B. Abdulrahman and Abdulrazak K. Umar Abstract
Background:
Many studies have been conducted on the genetic and epigenetic etiology of gestational diabetesmellitus (GDM) in the last two decades because of the disease ’ s increasing prevalence and role in global diabetesmellitus (DM) explosion. An update on the genetic and epigenetic etiology of GDM then becomes imperative tobetter understand and stem the rising incidence of the disease. This review, therefore, articulated GDM candidategenes and their pathophysiology for the awareness of stakeholders. Main body (genetic and epigenetic etiology, GDM):
The search discovered 83 GDM candidate genes, of which
TCF7L2 , MTNR1B , CDKAL1 , IRS1 , and
KCNQ1 are the most prevalent. Certain polymorphisms of these genes canmodulate beta-cell dysfunction, adiposity, obesity, and insulin resistance through several mechanisms.Environmental triggers such as diets, pollutants, and microbes may also cause epigenetic changes in these genes,resulting in a loss of insulin-boosting and glucose metabolism functions. Early detection and adequatemanagement may resolve the condition after delivery; otherwise, it will progress to maternal type 2 diabetesmellitus (T2DM) and fetal configuration to future obesity and DM. This shows that GDM is a strong risk factor forT2DM and, in rare cases, type 1 diabetes mellitus (T1DM) and maturity-onset diabetes of the young (MODY). Thisfurther shows that GDM significantly contributes to the rising incidence and burden of DM worldwide and itsprevention may reverse the trend.
Conclusion:
Mutations and epigenetic changes in certain genes are strong risk factors for GDM. For affectedindividuals with such etiologies, medical practitioners should formulate drugs and treatment procedures that targetthese genes and their pathophysiology.
Keywords:
Adiposity, Beta-cell dysfunction, Epigenetics, Insulin resistance, Obesity
Background
Pregnant women develop insulin resistance at certainstages owing to increased placenta hormones, but mostwomen overcome this condition by up-regulating insulinproduction through beta cell expansion [1]. Gestationaldiabetes mellitus (GDM) begins when a pregnant femaledoes not make the extra insulin needed to normalizeblood glucose during the second or third trimester ofpregnancy [1]. Sometimes the glucose intolerance maybe present before pregnancy, but not diagnosed [2, 3].Uncontrolled GDM can cause high blood pressure, type 2 diabetes mellitus (T2DM), and increased risks of vas-cular diseases in pregnant women [4, 5]. Intrauterine ex-posure to high blood glucose may program the offspringto develop diabetes or obesity later in life [6]. It may alsocause macrosomia, birth defects, preterm birth, and de-velopmental delay [7 – © The Author(s). 2020 Open Access
This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. * Correspondence: [email protected]; [email protected] Federal University Birnin Kebbi, PMB 1157 Birnin Kebbi, NigeriaFull list of author information is available at the end of the article
Egyptian Journal of MedicalHuman Genetics
Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:13(2020) 21:13
Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:13(2020) 21:13 https://doi.org/10.1186/s43042-020-00054-8
DM are at least seven times more predisposed toT2DM [14]. Moreover, almost half of pregnant femaleswith GDM will develop diabetes in a decade [14]. Off-spring of women with GDM are also 8 times more proneto diabetes or pre-diabetes [15]. These show that GDMcontributes immensely to the alarming incidence of dia-betes worldwide [16]. Diabetes affected about 451 mil-lion people in 2017, of which 5 million died and USD850 billion was spent on healthcare expenditure [17].Considering the impact of GDM, the reduction of itsprevalence and effective management of the affected willgo a long way in stemming the incidence and burden ofdiabetes. However, to achieve a reduced prevalence ofGDM, a proper understanding of its etiology is neces-sary. Fortunately, improved biological techniques in thelast two decades have led to more understanding of thegenetic and epigenetic etiology of the disease, thus anupdate becomes necessary. This review therefore articu-lated current findings on the genetic and epigenetic eti-ology of GDM.
Methods
Databases searched
An in-depth search of PubMed, Scopus, SpringerLink,Google Scholar, and ResearchGate databases was per-formed for relevant research articles on GDM.
Search terms
Some search terms used to retrieve articles are gesta-tional diabetes mellitus, hyperglycemia, insulin resist-ance, obesity, glucose metabolism, beta-cell dysfunction,and gestational diabetes genes. Other search terms usedinclude glucose insensitivity, epigenetics of diabetes mel-litus, gestational diabetes testing and cost-effectiveness,and the prevalence of gestational diabetes.
Article inclusion criteria
Inclusion criteria include the following:Research published in the English language.Research that focused on GDM.Studies that focused on the genetic and epigenetic eti-ology of GDM.Articles that centered on GDM testing and cost-effectiveness.Studies published between 2000 till date.
Article exclusion criteria
Exclusion criteria include the following:Studies that are not available in English language.Studies with only abstract available.Research that described GDM, but with no clear gen-etic and epigenetic mechanismsStudies published before the year 2000.
Results
Genetic etiology in GDM
The search found that mutations in some genes, or theirvariants, may interact with one another and environ-mental triggers to cause GDM (Fig. 1). The genetic eti-ology of GDM overlaps with T2DM, as most of theGDM candidate genes also predispose humans toT2DM. This explains the common pathophysiology ofGDM and T2DM as both express beta-cell dysfunctionand abnormal glucose metabolism [18]. Contrary tosome reports, GDM also shares common pathophysi-ology with type 1 diabetes mellitus (T1DM) andmaturity-onset diabetes of the young (MODY), but lessthan 10 % of GDM patients show these associations[18].Though many genes reportedly showed an associationwith obesity, insulin resistance, and beta-cell dysfunction,the present study discovered only 83 genes with a clearGDM pathophysiology and are presented in Table 1.
Most frequent GDM candidate genes
The list of GDM candidate genes is inexhaustible asmore genes are continually discovered; however, certaingenes are most often linked with the disease. Table 2shows the most frequent GDM candidate genes andtheir variants in various ethnic groups.From Table 2, we used a pie chart (Fig. 2) to expressthe percentage occurrence of each gene based on ethni-city.
TCF7L2 gene was the most frequent having presentin 17 % of the ethnics, followed by
MTNR1B with 15 %,
CDKAL1
10 %,
KCNQ1
10 %, and
IRS1
10 %. Someother genes are not widespread, but are often found incertain ethnics or regions. These genes include
ZRANB3 ,found in Africa [96];
ABCC8 found among Finnish[119];
Chemerin , found among Iranians [120]; and
INS ,found among the Greeks [121]. These genes can be usedto develop a genetic testing guideline to predict the like-lihood of GDM or determine its genetic and epigeneticetiology. This is important because there is no genetictesting procedure yet for GDM, partly because the con-dition is multifactorial in which several genes interactwith environmental triggers to cause the disease. Thus, amutation in a single gene may not explain full suscepti-bility to GDM and testing for all the candidate genes willbe expensive and cumbersome. The low prevalence ofGDM in the past also contributes to the lack of interestin developing a genetic testing guideline for the disease.
Epigenetic etiology in GDM
Epigenetics refers to the study of heritable changes inbiological processes caused by modification of chemicaltags on DNA such as methyl and ethyl groups [122].These modifications are mediated by some mechanisms,including DNA methylation, histone modification, and
Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:13(2020) 21:13
Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:13(2020) 21:13
Page 2 of 13 icroRNA expression [122]. Epigenetic mechanismsplay important roles in several cellular activities, but cer-tain environmental triggers can reprogram the epige-nome, resulting in disease pathologies [123]. Inparticular, epigenetic mechanisms regulate several genesthat maintain beta-cell morphology, proliferation, andfunctions, thus implies that epigenetic modification maydisrupt insulin secretion and sensitivity, causing meta-bolic diseases, including GDM [124, 125]. Epigeneticchanges are expressed in both somatic and gamete cells,and thus can be transmitted from generation to gener-ation [126].Studies have reported many instances of epigenetic modi-fications involving insulin synthesis and glucose metabolismin GDM. For instance, histone under-acetylation and over-methylation in the promoter region of the
PDX1 gene re-duce the insulin-boosting function of the gene [127]. Also,in a study that examined the methylation of the
IL-10 geneamong pregnant women, hypo-methylation of maternalblood cells and elevated plasma
IL-10 levels were noticed inwomen with GDM [128]. In another study that comparedthe miRNA profiles of some diabetic pregnant rats withnondiabetic, repression of miR-338 and overexpression of miR-451 were associated with reduced β -cell mass in thediabetic [129]. In vitro upregulation of miR-451 and repres-sion of miR-338 in the same study increased β -cell mass,leading to improved glucose metabolism [129]. In a studythat investigated the miRNA expressions of maternal andfetal blood cells of some pregnant women, 29 miRNAs wereupregulated in individuals with GDM [130]. Of these miR-NAs , miRNA-340 was confirmed to downregulate the ex-pression of the PAIP1 gene [130]. In vitro normalization ofthe miRNA-340 expression of the diabetic mothers in-creased insulin production [130].
Environmental triggers of genetic and epigenetic etiologyof GDM
Both the genetic and epigenetic etiology of GDM are me-diated by certain environmental triggers that change genefunctions. The genetic triggers mutate the genes, while theepigenetic triggers affect the chemical tags on the DNAwithout affecting the nucleotide sequence (Fig. 3). Amongthe environmental triggers are pollution and microbial ex-posures, whose GDM modulatory roles have been estab-lished by several studies. In a study that monitored theeffects of air pollution among pregnant Southern Califor-nians, prepregnancy exposures to nitrogen dioxide (NO ),particulate matter (PM2.5 and PM10), and dioxin were re-lated to GDM [131]. Nitrogen dioxide and particulatematter can cause oxidative stress, overexpression of proin-flammatory cytokines, and endothelial dysfunction, result-ing in increased insulin resistance [132]. Dioxincompounds can interact with peroxisome proliferator-activated receptor- γ ( PPARG ), disrupting insulin signalingpathways and resulting in insulin resistance and abnormalglucose metabolism [133]. Exposure to pathogenic micro-bial organisms may disrupt the gut microbiota and com-promise the immune system, leading to metabolicdisorders and GDM. Vu et al. [134] demonstrated in rab-bits that a toxin produced by
Staphylococcus aureus mayinteract with fat cells and the immune system, resulting ininflammation, insulin resistance and glucose intolerance[134]. In a study of the microbiota of some pregnantwomen, individuals with GDM showed gut microbiota im-balance containing majorly the phylum Actinobacteriaand the genus Collinsella, Rothia and Desulfovibrio [135].A balanced gut microbiota is necessary for optimum me-tabolism and the immune system. Aside from microbialinfection, other environmental factors that may disrupt
Fig. 1
Genetic etiology of gestational diabetes mellitus
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GDM predisposing genes showing locations and phathophysiology
Number Gene Full name Locus Pathophysiology1
TCF7L2
Transcription factor 7-like 2 10q2 Increases apoptosis, impairing insulin secretion [19].2
KCNQ1
Potassium voltage-gated channel sub-family Q member 1 11p15.5-15.4 It disrupts the influx of calcium into the channel, resulting in decreasedinsulin secretion [20].
Centaurin-delta-2/ ArfGAP with rhoGAPdomain, ankyrin repeat and PH domain1 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 endoplas-mic reticulum stress, causing islet dysfunction [24].7 IGFBP-1
Insulin like growth factor bindingprotein 1 7p12.3 Decreased blood levels of IGFBP-1 cause overexpression of IGF-I, result-ing in inflammation [25].8
IGFBP-2
Insulin like growth factor bindingprotein 3 2q35 Reduced expression of IGFBP-2 inhibits adipogenesis, leading to obesityand insulin resistance [26].9
IGF2BP2
Insulin like growth factor 2 mRNAbinding protein 2 3q27.2 Impairs β -cell function and modulates obesity, altering insulin sensitivity[27].10 IGFBP-3
Insulin like growth factor bindingprotein 3 7p12.3 Overexpression of IGFBP-3 predisposes to HBM body, disrupting glu-cose metabolism [28].11
IGFBP-4
Insulin like growth factor bindingprotein 4 17q21.2 Reduced levels cause HBM and insulin resistance [28].12
IGFBP5
Insulin like growth factor bindingprotein 5 2q35 Disrupts IGF-1 signaling pathway, leading to insulin insensitivity [29].13
PPARG
Peroxisome proliferator-activated recep-tor gamma 3p25.2 Stimulates abnormal fat deposition in tissues, causing obesity andinsulin resistance [27].14
KCNJ11
Potassium voltage-gated channel sub-family 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 in-sulin 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 cmember 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, leadingto high-fat deposition and insulin resistance [35].22
GLUT4/SLC2A4
Glucose transporter type 4/Solutecarrier 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 glucosemetabolism [38].25
PIK3R1/ PI3K
Phosphoinositide-3-kinase regulatorysubunit 1 5q13.1 Disrupts insulin signaling pathway in skeletal muscle and inhibit livergluconeogenesis [38].26
STRA6
Signaling receptor and transporter ofretinol 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 insulinresistance [40, 41].28
CDKAL1
Cyclin-dependent Kinase 5 Regulatorysubunit-associated protein 1-like 1 6p22.3 Inhibits the conversion of proinsulin to insulin through proteintranslation, leading to insulin resistance [42].29
GCK
Glucokinase 7p13 Increases body fat mass, resulting in insulin resistance [43].
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GDM predisposing genes showing locations and phathophysiology (Continued)
Number Gene Full name Locus Pathophysiology30
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 molecules[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 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
TPH1
Tryptophan hydroxylase 1 11p15.1 Causes low levels of serotonin, increasing weight gain and causinginsulin intolerance [56].43
HNF1A
Hepatocyte nuclear factor-1 alpha 12q24.31 Causes adiposity, leading to pre-pregnancy obesity and insulin resist-ance [57].45
GCKR
Glucokinase regulator 2p23.3 Overexpression of GCKR causes hyperactivity of GCK, reducing glucoseand increasing fat accumulation [58]. Loss of the function reduces GCKexpression, impairing glucose clearance [59].46
MIF
Macrophage migration inhibitory factor 22q11.23 Overexpression of the MIF gene in placental tissue causes insulinresistance [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 causinginsulin resistance [62].49
FTO
Fat mass and obesity-associated gene/Alpha-ketoglutarate dependentdioxygenase 16q12.2 Causes adiposity, leading to pre-pregnancy obesity and insulin resist-ance [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 glucosesignaling [65].52
IL-1 β 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 andlow insulin synthesis [67].54 IL-10
Interleukin-10 1q32.1 Overexpression compromises immune response, disrupting insulinmetabolism [68].55
PAX8
Paired box 8 2q14.1 Reduces islet viability and beta cell survival [69].56
ADIPOQ(diponectingene)
Adiponectin, C1Q and collagen domaincontaining 3q27.3 Causes low adiponectin, leading to obesity and insulin resistance [70].57
RARRES2(Chemeringene) retinoic acid receptor responder 2 7q36.1 Initiates inflammation and energy imbalance, leading to obesity andinsulin 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].
Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:13
Page 5 of 13 ut microbiota include certain diseases, oral microbiome,diets, and antibiotic use, among others [136].Lifestyles such as short sleep, poor nutritional choices,advanced age, and physical inactivity are some environmen-tal triggers that may predispose humans to GDM. Shorthour sleep at night can increase body fat accumulation, re-duce glucose metabolism, and predispose to T2DM andGDM. In a study that determines the frequency of GDM among sleep-deprived 668 Singaporeans, 131, representing19 %, were diagnosed with GDM of which 27.3 % sleep lessthan 6 hours a night, while 16.8 % sleep between 7-8 hours[137]. Poor nutrition, such as energy-dense western dietsmay cause overweight and obesity, disrupting insulin signal-ing pathways and insulin sensitivity. Saturated fats can dis-rupt insulin signaling, induce inflammation and endothelialdysfunction, resulting in GDM. In a study that evaluated
Table 1
GDM predisposing genes showing locations and phathophysiology (Continued)
Number Gene Full name Locus Pathophysiology60
APLN
Apelin Xq26.1 Causes a loss of energy balance, obesity, and insulin resistance [74].61
NUCB2(nesfatin 1gene)
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(Visfatingene)
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 Neu-roD, Mafa and GCK, and enhances beta-cell de-differentiating genesuch as PAX4 and REST [77].65
RREB1
Ras responsive element binding protein1 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 insulinresistance [79].69
PRLR
Prolactin receptor 5p13.2 Modulates loss of PRLR signaling in β -cells. reducing β -cell proliferationand 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 brownadipose tissues, causing glucose intolerance and insulin resistance [81].72
PAI-1
Plasminogen activator inhibitor 1 7q22 Predisposes to adiposity, increasing body weight and affectingpancreatic beta-cell function [82].73
TSPAN8
Tetraspanin-8 12q21.1 Impairs gestational glucose tolerance [83].74
G6PC2
Glucose-6-phosphatase catalytic subunit2 2q31.1 Elevates fasting glucose level and reduces insulin secretion [64].75
PTPRD
Protein tyrosine phosphatase receptortype d 9p24.1-p23 Disrupts insulin signaling pathway, leading to altered insulin sensitivityand glucose homeostasis [84].76
CRP
C-reactive protein 1q23.2 Overexpression causes obesity, resulting in systemic inflammation andinsulin 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 inlife [87].79
HDAC4
Histone deacetylase 4 2q37.3 Causes β -cell loss, leading to decreased insulin secretion. Also repressesbeta-cell transcriptional factors [88].80 FETUA/ AHSG
Fetuin-a 3q27.3 Increases body mass, insulin secretion and C-peptide levels, but lowerinsulin sensitivity [89].81
FETUB
Fetuin-b 3q27.3 Increases hepatic steatosis, impairing insulin secretion and glucosemetabolism [90].82
FGF21
Fibroblast growth factor 21 10q26.13 Cause an abnormal glucose metabolism independent of insulinresistance [91].83
SNORA8
An emerging candidate gene [92]
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Most prevalent gestational diabetes mellitus genes across countries, ethnicity, and race in the world
Gene Countries/ethnicity/race Variants Level of significance References
TCF7L2
Mexicans rs7901695 P = 2.16 × 10 − [93]rs7901696 P < 0.05 [93]rs7901697 P < 0.05 [93]rs7901698 P < 0.05 [93]Asians rs7903146 P = 0.001 [94]Scandinavians rs7903146 P < 0.05 [95]Africans rs7903146 P = 7.288 × 10 − [96]Hispanic/Latinos rs7903146 P < 0.05 [97]Caucasians/Danish rs7903146 P = 0.00017 [98]Caucasian rs4506565 P < 0.001 [99] KCNQ1
Mexicans rs2237892 P = 1.98 × 10 − [93]rs163184 P < 0.05 [93]rs2237897 P < 0.05 [93]Koreans rs2074196 P = 0.039 [100]rs2237892 P < 0.05 [100]East Asians rs2074196 P = 0.039 [100]rs2237892 P < 0.05 [100]Pakistan rs2237895 P < 0.05 [101] MTNR1B
Mexicans rs1387153 P = 0.05358 [93]Asians rs10830963 P < 0.001 [94]Caucasians rs10830963 P < 0.001 [94]Koreans rs10830962 P = 2.49 × 10 − [102]Danish rs10830963 P < 0.05 [103]rs1387153 P < 0.05 [103]Saudi Arabians rs1387153 P < 0.05 [104]rs10830963 P < 0.05 [104] PPARG
Asians rs1801282 P = 0.011 [94]Caucasians rs1801282 P < 0.05 [99]rs3856806 P < 0.05 [99]Caucasians/Danish rs1801282 P < 0.05 [98] CDKAL1
Koreans rs7754840 P = 2.49 × 10 − [102]Caucasians rs7756992 P < 0.05 [99]Caucasian/Danish rs7756992 P = 0.00017 [98]Iranians rs7754840 P < 0.001 [105] IRS1
Scandinavians IRS1 Arg972 P < 0.05 [106]Americans Arg972 P < 0.05 [107]Saudi Arabians rs1801278 P = 0.01 [108]Austro-Hungarians rs7578326 P < 0.05 [109] HMGA2
Africans rs138066904 P = 2.516 × 10 − [96]Africa Americans rs343092 P < 0.05 [96]Europeans rs2258238 P < 0.05 [96] IGF2BP2
Koreans rs4402960 P < 0.001 [110]Caucasians/Danish rs4402960 P < 0.001 [111]Chinese rs4402960 P < 0.001 [112] Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:13
Page 7 of 13 he effect of dietary patterns among pregnant Chinesewomen, diets containing high protein and low starch wereassociated with a reduced risk of GDM [138]. Energy-densediets are deficient in betaine, which is a methyl donor formethylating important biological processes and as well asubstrate of methionine metabolism [139]. Diets low inbetaine may induce abnormal methylation of some genesinvolved in insulin synthesis and glucose metabolism. Ad-vanced age may also predispose pregnant women to GDMbecause mitochondrial functions decline with age, leadingto reduced metabolic activities and an increased body massindex [140]. Aging changes the epigenetic pattern, affectingthe expression of some genes involved in glucose metabol-ism, particularly the
COX7A1 gene in the respiratory chain[141]. In a study of 1688 women in northwest London whodeveloped GDM, advanced maternal age was linked toGDM [142]. Studies that demonstrate the role of physicalinactivity in the pathogenesis of GDM are scarce. However,a systematic and meta-analysis by Ming et al. [143] showsthat physical activity during pregnancy can decrease the oc-currence of GDM, suggesting that lack of exercise is a riskfactor. Some mechanisms through which inactivity mediates diseases include mitochondrial dysfunction,changes in the composition of muscles, and insulin resist-ance, among others [144]. Physical inactivity influences theepigenome negatively, affecting several generations [145].
GDM testing, efficacy, and cost-effectiveness
Early detection of GDM is important to prevent its short-and long-term effects, especially the maternal progressionto T2DM and fetal programming to DM later in life. Cer-tain features such as BM1 above 30 kg/m as well as previ-ous GDM, baby birth weight of 4.5 kg or above, andmacrosomia suggest a need for a GDM test [146]. Preg-nant women with a family history of DM and ethnicgroups with a high prevalence of DM such as Asian, Black,African-Caribbean or Middle Eastern should also considerthe test [146, 147]. As stated earlier, there is no genetictesting procedure yet for GDM, however, two tests,namely glucose challenge test (GCT) and oral glucose tol-erance test (OGTT) are frequently conducted at 24-28weeks of pregnancy to diagnose GDM. The two tests canbe done in succession known as 2-step screening, orOGTT alone can be done called 1-step screening.In the 2-step screening, the GCT (otherwise known asa glucose screening test) is done first and entails testingthe blood glucose one hour after drinking a sweet sub-stance without fasting. If the blood glucose is 140 mg/dL(7.8 mmol/L) or higher, then an OGTT is necessary[148]. The OGTT measures blood glucose after 8-hourfasting, after which a glucose substance (75 g) is takenand blood glucose re-measured after 1, 2 and 3 hours.High blood glucose levels at any two or more of theblood test times suggest GDM [148]. Though the patho-physiology of GDM are similar with T2DM, a GCT of200 mg/dL or more could indicate T2DM [148].Relatively recently, serum levels of C-reactive protein(CRP) as well as glycated hemoglobin (HbA1c) and ran-dom blood sugar (RBS) are used as screening tools forGDM in the first trimester. CRP concentrations of about6 mg/L or higher in undiluted serum samples are con-sidered positive for GDM [149]. According to the Inter-national Association of the Diabetes and PregnancyStudy Group (IADPSG), the cutoff level of HbA1c is 6.5% and RBS is 11.1 mmol (200mg/dL) [150]. Table 2
Most prevalent gestational diabetes mellitus genes across countries, ethnicity, and race in the world (Continued)
Gene Countries/ethnicity/race Variants Level of significance References
GCKR
Malaysians rs780094 P < 0.05 [113]American Caucasians rs780094 P < 0.05 [114]Brazilians rs780094 P < 0.05 [115] FGF21
Iranians Over expression of mRNA P < 0.001 [116]Chinese Over expression of mRNA P < 0.001 [117]Australians Over expression of mRNA P < 0.001 [118] Fig. 2
Percentage prevalence of most implicated GDM genes fromdata extracted
Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:13
Page 8 of 13 he cost-effectiveness of GDM testing is controversialbecause it depends on the region, race, screening tools,and methods. A systematic review by Fitria [151] re-ported that GDM testing and controlling is not effectivein high-income countries. This could be due to the lowprevalence of the disease in the region and the all-encompassing health care system. However, GDM test-ing could be worthwhile in countries with a high preva-lence of GDM and nations with a poor healthcaresystem. For example, Marseille et al . [152] reported thecost-effectiveness of GDM testing using a devised modelin Israel and India, which are known for high GDM inci-dence rates. The 2-step GTT is often recommended,however, a systematic review and meta-analysis bySaconne et al [153] showed no significant cost-effectivedifference between the two methods. The 2-step screen-ing is also time-consuming and inconvenient, which mayput off some patients [150, 154]. Glycated hemoglobinand RBS are simple GDM screening tools and are gain-ing acceptance worldwide, however, more awareness andunderstanding of the tools are necessary.
Conclusion
Several articles reviewed showed that mutation and epi-genetic modifications in certain genes can predisposehumans to GDM. Most of the GDM candidate genesidentified have also been implicated in the pathogenesis ofT2DM, and both diseases share a common pathophysi-ology. The two metabolic disorders expressed oxidativestress-induced beta-cell dysfunction and insulin resistancethrough adiposity and obesity. One major difference be-tween GDM and T2DM is that it resolves most times afterdelivery, however, it may progress to T2DM if notchecked. This shows that GDM is a strong risk factor forT2DM, thus, its detection and management may reducethe prevalence of DM worldwide. Of the GDM candidategenes identified, the variants of
TCF7L2 , MTNR1B , CDKAL1 , IRS1 and
KCNQ1 are the most widespread,while some others are confined to certain ethnic groups.A genetic testing procedure can be developed aroundthese genes to predict the likelihood of GDM or deter-mine its genetic and epigenetic etiology. This will go along way in stemming the incidence of DM worldwide.
Abbreviations
CRP: C-reactive protein; DM: Diabetes mellitus; GCT: Glucose challenge test;GDM: Gestational diabetes mellitus; HbA1C: Glycated hemoglobin;IADPSG: International Association of the Diabetes and Pregnancy StudyGroup; MODY: Maturity onset diabetes of the young; NO : Nitrogen dioxide;OGTT: Oral glucose tolerance test; PM2.5: Particulate matter size 2.5;PM10: Particulate matter size 10; RBS: Random blood sugar; T1DM: Type 1diabetes mellitus; T2DM: Type 2 diabetes mellitus Acknowledgements
None.
Authors ’ contributions TY conceptualized, did the literature search, drafted the manuscript, and didcorrespondence. TS designed the article and did the literature search. YA didthe article selection and proofreading. AU did the article selection andproofreading. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details Federal University Birnin Kebbi, PMB 1157 Birnin Kebbi, Nigeria. Departmentof Zoology and Environmental Biology, Olabisi Onabanjo UniversityAgo-Iwoye, Ago-Iwoye, Ogun State, Nigeria. Department of Biochemistryand Molecular Biology, Federal University Birnin Kebbi, Birnin Kebbi, Nigeria.
Fig. 3
Epigenetic etiology of gestational diabetes mellitus
Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:13
Page 9 of 13 eceived: 14 November 2019 Accepted: 11 February 2020
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