Introduction
Maternal obesity and gestational diabetes mellitus (GDM) is a growing public health problem worldwide [
1]. The Institute of Medicine (IOM) developed guidelines for gestational weight gain (GWG) during pregnancy; however, no specific recommendations could be made for GDM and multiethnic differences [
2,
3]. Both pre-pregnancy obesity and excessive GWG are related to increased risk of maternal obesity and GDM [
3]. Becoming pregnant or gaining too much weight during pregnancy are the risk factors for adverse perinatal complications and increased risk for future metabolic disease in overweight/obese women, both for the mothers and their offspring [
1,
4]. Pre-pregnancy obesity and excessive GWG may have additive negative impact on maternal and neonatal outcomes in women with GDM [
5,
6]. Pre-pregnancy obesity, gestational diabetes, and excessive GWG are associated with multiple factors such as the environment, behavior, and genetics; however, understanding these associations is complex [
1,
3]. Diabetes-related or maternal and/or fetal adiposity-related genetic variants have been associated with GDM, pre-pregnancy weight, and GWG during pregnancy [
7‐
9]. Kawai et al. reported that common type 2 diabetes risk variants were associated with increased risk of GDM [
8]. Genetic variants were associated with GDM and progression to pre-diabetes and type 2 diabetes mellitus in women with prior GDM [
9]. Evidence has been presented for a genetic predisposition to GDM risk and also a change in GWG during pregnancy [
7,
10‐
13], and gene–environment interactions could explain the variation in GWG and GDM.
The fat mass and obesity-associated gene (
FTO) rs9939609 single nucleotide polymorphism (SNP) was associated with increased risk of obesity and type 2 diabetes, as well as GDM [
10]. The
FTO SNPs have been reported to be associated with pre-pregnancy obesity [
8] and excessive GWG [
11]. The
FTO variants related to type 2 diabetes are mediated by the effect of the FTO gene on body mass index (BMI); however, the exact mechanisms of this relation have not been identified [
10,
11]. Vitamin D shows its cellular activity by binding to vitamin D receptors (VDR). VDR, as a transcription factor, has a role in the regulation of insulin secretion from pancreatic beta cells [
14]. VDR has effect on proliferation, differentiation, and activation of immune cells and cytokine production, and subsequently type 2 diabetes occurs [
15,
16]. Hepatocyte nuclear factor 1A (HNF1A), as a transcription factor, has a role in the function of pancreas beta cells [
17]. Endocrine and exocrine pancreatic cells express HNF1A in the developmental stage. HNF1A is necessary for the glucose response to insulin secretion and glucose metabolism [
18]. Women with
HNF1A mutation are diagnosed as having monogenic form of diabetes type 3 (MODY3), and these women usually present with GDM, and diabetes persisting after delivery [
17‐
19].
This is the first study to investigate the effect of
HNF1A gene,
VDR gene, and
FTO gene variants on having GDM, pre-pregnancy obesity, and excessive GWG in Turkey. We aimed to examine whether these genetic variants would associate with having GDM, and then, whether the genetic variants that associated with GDM would associate with adiposity including pre-pregnancy obesity and excessive GWG. The
VDR gene (encoding as SNPs p.BsmI, p.ApaI, p.TaqI, and p.FokI), and,
HNF1A gene (encoding as SNPs p.I27L, p.A98V, and p.S487N) were chosen because these genetic variants have been reported to be associated with type 2 diabetes, as well as GDM risk [
12,
14‐
20]. We also investigated the obesity-related
FTO gene rs9939609 SNP because it is associated with both GDM and gestational body weight during pregnancy [
10,
13,
20]. Genetic variants are implicated in the pathogenesis of GDM. Evidence suggests the genetic alterations in genes responsible for metabolic changes during pregnancy predispose to GDM [
7]. We also hypothesized that these diabetes and adiposity-related genetic variants would likely be associated with GDM risk and gestational body weight during pregnancy.
Results
The mean age, gestational age, and height were similar between the women with GDM and controls (p > 0.05). Pre-pregnancy overweight/obesity were increased in women with GDM compared with controls (p < 0.05). Weight at delivery and excessive GWG were increased in women with GDM compared with the controls (p < 0.05). Serum glucose, insulin, HOMA-IR, and HbA1c were increased in women with GDM compared with the controls (p < 0.05, each). The clinical features of the subjects are shown in Table
1. Minor allele frequency of the
HNF1A,
VDR, and
FTO genes is shown in Table
2. These frequencies were in HWE except p.A98V. Haploview analysis showed that the
HNF1A, VDR, and
FTO genes were not in LD. The risk alleles of the
HNF1A gene (p.S487N, and p.A98V) and,
VDR gene (p.ApaI, p.TaqI, p.BsmI and p.FokI) were similar between women with GDM and the controls (p > 0.05, each). Genotype analysis is shown in Table
3.
Table 1
Characteristics of subjects
Age (year) | 28.25 ± 5.15 | 29.35 ± 5.36 | 0.075 |
Gestational age (weeks) | 26.27 ± 1.48 | 25.99 ± 1.65 | 0.137 |
Height (cm) | 160.40 ± 5.71 | 159.21 ± 5.95 | 0.076 |
Pre-pregnancy weight (kg) | 61.74 ± 11.98 | 76.21 ± 11.27 |
0.001
|
Pre-pregnancy BMI (kg/m2) | 24.06 ± 4.82 | 30.21 ± 5.10 |
0.001
|
Pre-pregnancy BMI (%) | | |
0.001
|
Underweight (< 20 kg/m2) | 23.4 | 3.8 | |
Normal weight (20–24.9 kg/m2) | 38.6 | 8.8 | |
Overweight (25–29.9 kg/m2) | 26.2 | 34.4 | |
Obesity (≥ 30 kg/m2) | 11.7 | 53.1 | |
Pre-pregnancy overweight/obesity (%)a | 37.9 | 87.5 |
0.001
|
Weight at delivery (kg) | 77.60 ± 12.59 | 87.58 ± 11.54 |
0.001
|
BMI at delivery (kg/m2) | 30.24 ± 5.18 | 34.71 ± 5.30 |
0.001
|
Gestational weight gain (kg) | 16.05 ± 5.43 | 11.56 ± 2.72 |
0.001
|
Gestational weight gain (%)b | | |
0.011
|
Excessive | 44.1 | 61.2 | |
Adequate | 46.9 | 33.1 | |
Below | 9.0 | 5.6 | |
Glucose (mg/dl) | 72.39 ± 7.12 | 101.67 ± 11.99 |
0.001
|
İnsulin (µIU/ml) | 8.07 ± 2.02 | 11.93 ± 4.78 |
0.001
|
HOMA-IR | 1.42 ± 0.39 | 3.06 ± 1.26 |
0.001
|
HbA1c (%) | 5.01 ± 0.32 | 5.51 ± 0.43 |
0.001
|
Systolic BP (mmHg) | 108.06 ± 8.74 | 110.84 ± 11.23 | 0.052 |
Diastolic BP (mmHg) | 72.70 ± 5.62 | 73.48 ± 5.11 | 0.207 |
Table 2
Minor allele frequency of polymorphisms
HNF1A I27L rs1169288 | T | 0.44 |
HNF1A S487N rs2464196 | T | 0.37 |
HNF1A A98V rs1800574 | T | 0.10 |
VDR ApaI rs7975232 | C | 0.42 |
VDR TaqI rs731236 | C | 0.35 |
VDR BsmI rs1544410 | G | 0.45 |
VDR FokI rs2228570 | T | 0.35 |
FTO rs9939609 | A | 0.37 |
Table 3
Genotype analysis of HNF1A gene, VDR gene and FTO gene polymorphisms
FTO gene rs9939609 (%) | | | | 0.011* |
Co-dominant wild type TT | 73 | 59 | | |
Heterozygous AT | 54 | 62 | 1.42 (0.86–2.24) | 0.169** |
Homozygous AA | 18 | 39 | 2.68 (1.39–4.13) | 0.003*** |
Dominant (AT + AA/TT) | 72 vs. 73 | 101 vs. 59 | 1.73 (1.12–2.74) |
0.018
|
Recessive (AA/AT + TT) | 18 vs. 127 | 39 vs. 121 | 2.27 (1.23–4.19) |
0.007
|
HNF1 gene I27L rs1169288 (%) | | | | 0.009* |
Co-dominant wild type GG | 50 | 33 | | |
Heterozygous GT | 78 | 94 | 1.82 (1.13–3.12) | 0.026** |
Homozygous TT | 17 | 33 | 2.94 (1.41–4.16) | 0.003*** |
Dominant (GT + TT/GG) | 95 vs. 50 | 127 vs. 33 | 2.02 (1.21–3.38) |
0.007
|
Recessive (TT/GT + GG) | 17 vs. 128 | 33 vs. 127 | 1.95 (1.13–3.49) |
0.036
|
HNF1 gene S487N rs2464196 (%) | | | | 0.919* |
Co-dominant wild type CC | 61 | 64 | | |
Heterozygous CT | 62 | 72 | 1.10 (0.67–1.80) | 0.684** |
Homozygous TT | 22 | 24 | 1.04 (0.52–2.04) | 0.910*** |
Dominant (CT + TT/CC) | 84 vs. 61 | 96 vs. 64 | 1.11 (0.70–1.76) | 0.683 |
Recessive (TT/CT + CC) | 22 vs. 123 | 24 vs 136 | 0.98 (0.52–1.84) | 0.966 |
HNF1 gene A98V rs1800574 (%) | | | | 0.433* |
Co-dominant wild type CC | 121 | 130 | | |
Heterozygous CT | 22 | 24 | 1.01 (0.54–1.90) | 0.962** |
Homozygous TT | 2 | 6 | 2.79 (0.55–12.45) | 0.196*** |
Dominant model (CT + TT/CC) | 24 vs. 121 | 30 vs. 130 | 1.16 (0.64–2.10) | 0.615 |
Recessive model (TT/CT + CC) | 2 vs. 143 | 6 vs. 154 | 2.78 (0.55–12.5) | 0.196 |
VDR gene ApaI rs7975232 (%) | | | | 0.199* |
Co-dominant wild type AA | 52 | 48 | | |
Heterozygous AC | 73 | 78 | 1.15 (0.69–1.91) | 0.571** |
Homozygous CC | 20 | 34 | 1.84 (0.93–3.62) | 0.076*** |
Dominant (AC + CC/AA) | 93 vs. 52 | 112 vs. 48 | 1.30 (0.80–2.10) | 0.279 |
Recessive (CC/AA + AC) | 20 vs. 125 | 34 vs. 126 | 1.68 (0.92–3.02) | 0.088 |
VDR gene TaqI rs731236 (%) | | | | 0.472* |
Co-dominant wild type TT | 82 | 81 | | |
Heterozygous CT | 33 | 37 | 1.13 (0.64–1.98) | 0.658** |
Homozygous CC | 30 | 42 | 1.41 (0.80–2.48) | 0.222*** |
Dominant (CT + CC/TT) | 63 vs. 82 | 79 vs. 81 | 1.26 (0.82–2.04) | 0.301 |
Recessive (CC/CT + TT) | 30 vs. 115 | 42 vs. 118 | 1.36 (0.81–2.32) | 0.253 |
VDR gene BsmI rs1544410 (%) | | | | 0.461* |
Co-dominant wild type AA | 57 | 53 | | |
Heterozygous AG | 52 | 63 | 1.32 (0.78–2.24) | 0.290** |
Homozygous GG | 36 | 45 | 1.37 (0.76–2.44) | 0.284*** |
Dominant (AG + GG/AA) | 88 vs. 57 | 108 vs. 53 | 1.34 (0.841–2.15) | 0.215 |
Recessive (GG/AG + AA) | 36 vs. 109 | 45 vs. 116 | 1.18 (0.71–1.97) | 0.515 |
VDR gene FokI rs2228570 (%) | | | | 0.191* |
Co-dominant wild type CC | 78 | 76 | | |
Heterozygous CT | 43 | 44 | 1.05 (0.62–1.77) | 0.855** |
Homozygous TT | 24 | 40 | 1.71 (0.94–3.10) | 0.076*** |
Dominant (CT + TT/CC) | 67 vs. 78 | 84 vs. 76 | 1.28 (0.82–2.01) | 0.272 |
Recessive (TT/CT + CC) | 24 vs. 121 | 40 vs. 120 | 1.68 (0.95–2.59) | 0.070 |
The
FTO gene rs9939609 distribution was TT-wild, heterozygote AT, and homozygote AA at 50.3%, 37.2%, and 12.4% in the controls, and 36.9%, 38.8%, and 24.4% in women with GDM (p = 0.011). The
FTO gene AA genotype was associated with an increased risk of GDM more than the TT/AT genotype in co-dominant, dominant, and recessive models (dominant: AT + AA vs. TT-wild, 63.1% vs. 49.7%, OR = 1.73, 95% CI [1.12–2.74], p = 0.018, and recessive: AA vs. AT + TT, 24.4 vs. 12.4%, OR = 2.27, 95% CI [1.23–4.19], p = 0.007) (Table
3). The
FTO AA/AT genotype had a greater association with pre-pregnancy overweight/obesity than TT-wild genotype (p < 0.05) (Table
4). Pre-pregnancy weight (p < 0.05) and weight at delivery (p < 0.05) progressively increased from the AA genotype to the TT genotype. GWG was increased in AT/AA genotype compared with the TT genotype (p < 0.05). Serum glucose, insulin, HOMA-IR, and HbA1c were higher in the AA genotype compared with the TT genotype (p < 0.05). The
FTO AA genotype was associated with a greater risk of pre-pregnancy overweight/obesity compared with AT/TT genotypes (OR = 1.43, 95% CI [1.25–3.4], p = 0.035). The
FTO AA genotype was associated with excessive GWG risk compared with the TT and AT genotype (OR = 1.73, 95% CI [1.62–3.15], p = 0.034); however, this association was lost after adjusting for pre-pregnancy weight (OR = 1.1, 95% CI [0.94–2.38], p > 0.05).
Table 4
Clinics of pregnants according to the FTO gene rs9939609 SNP
Controls (%) | 55.3 (n = 73) | 46.6 (n = 54) | 31.6 (n = 18) | 0.169 |
0.003
| 0.060 |
Gestational diabetes mellitus (%) | 44.7 (n = 59) | 53.4 (n = 62) | 68.4 (n = 39) | | | |
Pre-pregnancy BMI (%) | | | | < 0.001 |
0.001
|
0.011
|
Underweight (< 20 kg/m2) | 18.2 | 10.3 | 7.0 | | | |
Normal weight (20–24.9 kg/m2) | 33.3 | 16.4 | 12.3 | | | |
Overweight (25–29.9 kg/m2) | 19.7 | 44.8 | 26.3 | | | |
Obesity (≥ 30 kg/m2) | 28.8 | 28.4 | 54.4 | | | |
Pre-pregnancy overweight/obesity (%)a | 48.5 (n = 64) | 73.3 (n = 85) | 80.7 (n = 46) | < 0.001 |
0.001
| 0.284 |
Gestational weight gain (%)b | | | |
0.001
| < 0.001 |
0.014
|
Below | 12.1 | 3.4 | 3.6 | | | |
Adequate | 51.5 | 37.9 | 16.1 | | | |
Excessive | 36.4 | 58.6 | 80.4 | | | |
Excessive GWG (%) | 36.4 (n = 48) | 58.6 (n = 68) | 80.4 (n = 46) |
0.001
| < 0.001 |
0.003
|
Pre-pregnancy weight (kg) | 65.79 ± 13.80 | 69.69 ± 11.31 | 76.78 ± 14.81 |
0.016
| < 0.001 |
0.001
|
Pre-pregnancy BMI (kg/m2) | 25.80 ± 5.80 | 27.46 ± 5.03 | 30.36 ± 6.27 |
0.017
| < 0.001 |
0.001
|
Weight at delivery (kg) | 78.52 ± 13.01 | 83.84 ± 9.80 | 90.78 ± 14.79 |
0.001
| < 0.001 | < 0.001 |
BMI at delivery (kg/m2) | 30.77 ± 5.56 | 33.03 ± 4.72 | 35.86 ± 6.22 |
0.001
| < 0.001 |
0.001
|
Gestational weight gain (kg) | 10.93 ± 3.77 | 12.93 ± 2.31 | 13.98 ± 4.91 |
0.029
|
0.021
| 0.654 |
Glucose (mg/dl) | 84.64 ± 18.01 | 88.06 ± 17.65 | 91.64 ± 17.25 | 0.134 |
0.014
| 0.207 |
İnsulin (µIU/ml) | 9.61 ± 4.35 | 10.18 ± 3.72 | 11.27 ± 4.89 | 0.315 |
0.039
| 0.148 |
HOMA-IR | 2.16 ± 1.26 | 2.33 ± 1.18 | 2.65 ± 1.37 | 0.307 |
0.033
| 0.159 |
HbA1c (%) | 5.22 ± 0.48 | 5.24 ± 0.41 | 5.41 ± 0.51 | 0.685 |
0.018
|
0.027
|
Systolic BP (mmHg) | 110.41 ± 9.59 | 108.87 ± 10.61 | 108.77 ± 10.74 | 0.232 | 0.298 | 0.951 |
Diastolic BP (mmHg) | 73.74 ± 5.43 | 72.81 ± 5.03 | 72.24 ± 5.75 | 0.169 | 0.090 | 0.503 |
The
HNF1A gene p.I27L distribution of GG-wild, GT, and TT was 34.5%, 53.8%, and 11.7% in the controls, and 20.6%, 58.8%, and 20.6% in women with GDM (p = 0.009). The
HNF1A gene p.I27L TT/GT genotype was associated with a greater risk of GDM in comparison with the GG genotype in co-dominant, dominant, and recessive models (dominant: GT + TT vs. GG-wild, 79.4 vs. 65.5%, OR = 2.02, 95% CI [1.21–3.38], p = 0.007 and recessive: TT vs. GT + GG, 20.6 vs. 11.7%, OR = 1.95, 95% CI [1.13–3.49], p = 0.036) (Table
3). Pre-pregnancy weight, weight at delivery, and GWG were similar between p.I27L genotypes (p > 0.05) (Table
5). Glucose, HOMA-IR, and HbA1c were increased in the p.I27L TT genotype compared with the GG-wild type (p < 0.05). Pre-pregnancy weight, weight at delivery, and GWG did not differ between the
VDR and
HNF1A gene carriers (p > 0.05).
Table 5
Clinics of pregnant women according to the HNF1A gene p.I27L
Controls (%) | 60.2 (n = 50) | 45.3 (n = 78) | 34.0 (n = 17) |
0.026
|
0.003
| 0.153 |
Gestational diabetes mellitus (%) | 39.8 (n = 33) | 54.7 (n = 94) | 66.0 (n = 33) | | | |
Pre-pregnancy BMI (%) | | | | 0.653 | 0.622 | 0.695 |
Underweight (< 20 kg/m2) | 15.7 | 13.4 | 8.0 | | | |
Normal weight (20–24.9 kg/m2) | 21.7 | 23.3 | 24.0 | | | |
Overweight (25–29.9 kg/m2) | 33.7 | 27.9 | 34.0 | | | |
Obesity (≥ 30 kg/m2) | 28.9 | 35.5 | 34.0 | | | |
Pre-pregnancy overweight/obesity (%)a | 62.7 (n = 52) | 63.4 (n = 109) | 68.0 (n = 34) | 0.911 | 0.532 | 0.547 |
Gestational weight gain (%)b | | | | 0.112 | 0.804 | 0.342 |
Below | 3.6 | 9.4 | 6.0 | | | |
Adequate | 45.8 | 35.1 | 46.0 | | | |
Excessive | 50.6 | 55.6 | 48.0 | | | |
Excessive GWG (%) | 50.6 (n = 42) | 55.8 (n = 96) | 48.0 (n = 24) | 0.434 | 0.771 | 0.329 |
Pre-pregnancy weight (kg) | 67.93 ± 13.64 | 70.12 ± 14.28 | 68.94 ± 11.42 | 0.247 | 0.665 | 0.592 |
Pre-pregnancy BMI (kg/m2) | 26.78 ± 5.74 | 27.51 ± 6.06 | 27.35 ± 5.24 | 0.364 | 0.568 | 0.870 |
Weight at delivery (kg) | 81.84 ± 13.34 | 83.56 ± 13.50 | 81.98 ± 10.73 | 0.338 | 0.951 | 0.445 |
BMI at delivery (kg/m2) | 32.25 ± 5.66 | 32.77 ± 5.88 | 32.50 ± 5.13 | 0.503 | 0.795 | 0.772 |
Gestational weight gain (kg) | 14.02 ± 4.60 | 13.67 ± 4.83 | 13.24 ± 4.98 | 0.583 | 0.359 | 0.434 |
Glucose (mg/dl) | 83.89 ± 17.10 | 86.88 ± 17.69 | 94.06 ± 18.23 | 0.203 |
0.002
|
0.013
|
İnsulin (µIU/ml) | 9.52 ± 3.16 | 10.30 ± 4.76 | 10.64 ± 4.09 | 0.215 | 0.108 | 0.681 |
HOMA-IR | 2.10 ± 1.01 | 2.36 ± 1.37 | 2.54 ± 1.23 | 0.155 |
0.045
| 0.470 |
HbA1c (%) | 5.15 ± 0.40 | 5.29 ± 0.50 | 5.32 ± 0.41 |
0.048
|
0.037
| 0.736 |
Systolic BP (mmHg) | 109.93 ± 10.07 | 109.27 ± 10.26 | 109.70 ± 10.37 | 0.626 | 0.896 | 0.797 |
Diastolic BP (mmHg) | 73.20 ± 5.47 | 73.11 ± 5.26 | 72.94 ± 5.63 | 0.901 | 0.790 | 0.838 |
Discussion
Both the FTO AA genotype and HNF1A p.I27L GT/TT genotype were associated with an increased risk of having GDM in Turkish women. However, the VDR gene (p.ApaI, p.TaqI, p.FokI, p.BsmI) and HNF1A gene (p.A98V, p.S487N) were not associated with having GDM. Insulin resistance and impaired glucose metabolism was observed in both p.I27L TT and FTO AA genotype carriers. The FTO AA genotype was associated with an increased risk for pre-pregnancy overweight/obesity, but not associated with excessive GWG after adjusting for pre-pregnancy weight. The association of the adiposity-related gene FTO with GDM might be mediated by the effect of FTO on pre-pregnancy obesity. The diabetes-related p.I27L gene was associated with GDM by increasing insulin resistance.
Our results demonstrated that the
VDR gene p.ApaI, p.TaqI, p.BsmI, and p.FokI genotypes were not associated with having GDM in Turkish women. The
VDR gene and
HNF1A gene SNPs were not associated with pre-pregnancy weight, weight at delivery, and GWG during pregnancy. The associations of the
VDR gene and
HNF1A gene with pre-pregnancy weight, weight at delivery, and GWG have not been investigated in previous studies. El-Beshbishy et al. reported that p.BsmI and p.FokI were not associated with GDM in Saudi women [
22]. Incompatible to our results, p.FokI [
23], p.ApaI, and p.TaqI [
22] were associated with an increased risk of GDM in Iranian women [
24]. We found that the
HNF1A gene p.A98V and p.S487N were not associated with GDM in Turkish women. Zurawek et al. reported that p.I27L, p.A98V, and p.S487N were not associated with GDM in Polish women [
25]. No relationship was reported between p.A98V and GDM in Danish women [
12]; however, insulin secretion was decreased in p.A98V carriers without GDM [
26], which is compensated by increasing insulin sensitivity [
27]. Our data show that the
HNF1A gene p.I27L GT/GG genotype was associated with an increased risk of GDM (OR = 2.02, 95% CI [1.21–3.38], p = 0.007). Pre-pregnancy weight, weight at delivery, and GWG were not associated with p.I27L genotypes. Insulin resistance and impaired glucose metabolism was observed in p.I27L TT carriers. We suggest that the diabetes-related p.I27L gene was associated with the increased risk of GDM by impairing glucose metabolism and increasing insulin resistance. Similarly, p.I27L was associated with an increased GDM risk in Scandinavian women by the effect of p.I27L on pancreas beta cell function [
28] and insulin resistance [
29]. Decreased beta cell function/transcriptional activity, decreased glucose-stimulated insulin secretion, increased insulin resistance, and increased type2 diabetes risk have been found in p.I27L + p.S487N carriers (if also including p.A98V) [
27,
30,
31]. HNF1A controls beta cell function by regulating target genes such as glucose transporter 2, liver pyruvate kinase, collectrin, hepatocyte growth factor activator, and
HNF4A. Decreased HNF1A activity causes decreased beta cell mass and expression of these target genes, which lead to impaired insulin secretion [
17,
18]. Beta-cell dysfunction is more prone to developing impaired glucose tolerance during pregnancy [
28].
The
FTO gene AA genotype was associated with an increased risk of having GDM (OR = 2.27, 95% CI [1.23–4.19], p = 0.007). The
FTO AA genotype had a greater risk for pre-pregnancy overweight/obesity (OR = 1.43, 95% CI [1.25–3.4], p = 0.035). The
FTO AA genotype was not associated with GWG after adjusting for pre-pregnancy weight (OR = 1.1, 95% CI [0.94–2.38], p > 0.05). Insulin resistance and impaired glucose metabolism were observed in
FTO AA genotype carriers. We suggest that the adiposity-related gene
FTO was associated with increased risk of GDM by increasing pre-pregnancy obesity. Similarly, previous studies have shown that the
FTO rs9939609 AA genotype was associated with higher pre-pregnancy weight [
10,
13,
32]. Lawlor et al. reported that maternal fat or fetal fat adiposity-related variants were not associated with excessive GWG, but the
FTO gene was associated with pre-pregnancy overweight [
33]. The
FTO gene has a role in the regulation of adiposity-related phenotypes through the effect of FTO on weight gain during younger ages [
34] and continues throughout life [
10]. FTO is expressed in the hypothalamic region, which regulates appetite [
35], and this would contribute to energy intake and body fat mass [
36]. Our data demonstrated that
FTO gene AA genotype carriers were heavier before pregnancy, but AA carriers did not have significant weight gain during pregnancy. Chiou et al. reported that the
FTO gene was associated with pre-pregnancy obesity and a tendency to gain less weight throughout pregnancy [
5]. Consistent with our data, the
FTO gene was not associated with greater GWG after adjusting for pre-pregnancy BMI in Caucasian and African-American populations [
37]. The
FTO gene was not associated with GWG according to the period of pregnancy in British [
33] and Brazilian women [
10]. Moreover, GWG comprises other factors such as the fetus, amniotic fluid, and placenta [
10]. Pregnant women have biologic, behavioral, and hormonal changes throughout pregnancy [
11]. Pre-pregnancy body weight shows maternal nutritional changes before conception, whereas GWG represents fetal-maternal physiologic conditions associated with genetic and nutrition factors [
1]. This could modify the genetic contributions of the maternal
FTO,
HNF1A, and
VDR gene variants on pre-gestational weight and GWG, as well as GDM [
13,
33]; however it is not fully known which of these conditions is more associated with these disorders.
There are some limitations in our study that should be considered. We did not report the GWG according to gestational weeks. The small sample size resulted in a lower power for investigating a significant effect of any of the HNF1A, VDR, and FTO gene SNPs on weight changes during pregnancy. Also, we did not control our data for confounding variables such as nutrition, education, smoking and parity.
Conclusion
Both the FTO AA genotype and HNF1A p.I27L GT/TT genotype were associated with increased GDM risk in Turkish pregnant women. However, the VDR gene p.ApaI, p.TaqI, p.FokI, p.BsmI and the HNF1A gene p.A98V, p.S487N genotypes were not associated with having GDM. The diabetes-related p.I27L gene was associated with GDM by increasing insulin resistance. The diabetes-related HNF1A p.I27L gene was associated with insulin resistance, which might contribute to developing GDM. The FTO AA genotype was associated with pre-pregnancy overweight/obesity, but did not contribute to significant weight gain during pregnancy. The adiposity-related gene FTO was associated with GDM by the effect of FTO on pre-pregnancy obesity. The FTO gene was associated with pre-pregnancy obesity, which might contribute to developing GDM. Genetic factors involved in GDM, pre-pregnancy weight, and GWG should be identified for the prevention of adverse complications of GDM and obesity during pregnancy. Further studies with multiethnic and larger populations are needed to find genetic variants related to GDM, pre-pregnancy obesity, and GWG during pregnancy.
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