Homozygous AA Genotype of IL-17A and 14-bp Insertion Polymorphism in HLA-G 3′UTR Are Associated with Increased Risk of Gestational Diabetes Mellitus
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population and Design
2.2. Samples and DNA Extraction
2.3. HLA-G 14pb Gene Polymorphisms
2.4. IL-17A/RA Gene Polymorphisms
2.5. Statistical Analysis
3. Results
3.1. Clinical Data
3.2. Genotype and Allelic Frequency
3.3. Distribution Models
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
GDM | Gestational Diabetes Mellitus |
HLA-G | Human leukocyte antigen |
MHC | Major histocompatibility complex |
UTR | Untranslated region |
sHLA-G | Soluble human leukocyte antigen |
indel | Insertion/Deletion polymorphism |
Ins | Insertion |
Del | Deletion |
IL-1β | Interleukin-1β |
TNF-α | Tumor necrosis factor α |
IL-6 | Interleukin-6 |
IL-17 | Interleukin-17 |
SNP | Single Nucleotide Polymorphism |
OGTT | Oral glucose tolerance test |
ADA | American Diabetes Association |
gDNA | Genomic DNA |
PCR–RFLP | Polymerase chain reaction-restriction fragment length polymorphism |
BMI | Body mass index |
HWE | Hardy-Weinberg Equilibrium |
NFAT | Nuclear factor of activated T cells |
AP-1 | Activator protein 1 |
STAT3 | Signal transducer and activator of transcription 3 |
AhR | Aryl hydrocarbon receptor |
IRF4 | Interferon regulatory factor 4 |
T1DM | Type 1 diabetes mellitus |
T2DM | Type 2 diabetes mellitus |
ILT | Immunoglobulin-like transcript 2 |
Tregs | Regulatory T cells |
References
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Gene | Primer Sequences (Forward, Reverse) | Cycles | Annealing Temperature (°C) | Product Size (bp) |
---|---|---|---|---|
IL-17A | F: AGGTACATGACACCAGAAGACC | 35 | 60 | 514 |
R: TGCCCACGGTCCAGAAATAC | ||||
IL-17RA | F: GGAAGAGAGGAGAGGCGAAT | 35 | 60 | 430 |
R: CACCCCTTTGCCTGGTTCTG | ||||
HLA-G | F: TGTGAAACAGCTGCCCTGTGT | 30 | 56 | 345 (Del) |
R: GTCTTCCATTTATTTTGTCTCT | 359 (Ins) |
Variables | Group | p Value 1 | Total | |
---|---|---|---|---|
GDM | Control | |||
N, % | 79 (50.0%) | 79 (50.0%) | 158 (100.0%) | |
Current pregnancy | ||||
Age, years | 31 (26–35) | 30 (25–35) | 0.240 | 31 (25–35) |
Age, >25 years | 61 (77.2%) | 57 (70.4%) | 0.325 | 116 (73.4%) |
Gestational age, we. | 32 (27–36) | 33 (24–36) | 0.980 | 32 (25–36) |
Fasting glucose, mg/dL | 97 (90–106) | 85 (79–90) | 0.001 | 90 (82–98) |
Glucose, ≥95 mg/dL | 45 (57.0%) | 9 (10.1%) | 0.000 | 53 (33.5%) |
BMI, kg/m2 | 31.3 (28–35) | 28 (26–31) | 0.001 | 29.5 (27.1–33.2) |
Gestational BMI, n (%) | ||||
Low weight | 4 (5.1%) | 8 (10.1%) | 0.003 | 12 (7.6%) |
Suitable | 15 (19.0%) | 23 (29.1%) | 38 (24.0%) | |
Overweight | 25 (31.6%) | 34 (43.0%) | 59 (37.3%) | |
Obesity | 35 (44.3%) | 14 (17.7%) | 49 (31.0%) | |
Obesity/Overweight, n (%) | 60 (75.9%) | 48 (60.7%) | 0.060 | 108 (68.3%) |
Obesity, n (%) | 35 (44.3%) | 14 (17.7%) | 0.000 | 49 (31.0%) |
Obstetric background | ||||
Children | 63 (79.7%) | 48 (60.7%) | 0.014 | 111 (70.2%) |
Abortion | 29 (36.7%) | 31 (39.2%) | 0.870 | 60 (38.0%) |
GDM diagnosis | 6 (7.6%) | 0 (0.0%) | 0.028 | 8 (3.8%) |
Family history of DM | 59 (75.6%) | 66 (84.6%) | 0.228 | 125 (79.1%) |
Gene | SNP | HWE | Allele/Genotype | Group | |
---|---|---|---|---|---|
0.0223031 | GDM | Control | |||
A | 38 (24.1%) | 25 (15.8%) | |||
G | 120 (75.9%) | 133 (84.2%) | |||
IL-17A (-197G>A) | rs2275913 | G/G | 50 (63.3%) | 56 (70.9%) | |
G/A | 20 (25.3%) | 21 (26.6%) | |||
A/A | 9 (11.4%) | 2 (2.5%) | |||
0.03841204 | G | 50 (31.6%) | 45 (28.5%) | ||
A | 108 (68.4%) | 113 (71.5%) | |||
IL-17RA (-947A>G) | rs4819554 | A/A | 39 (49.4%) | 44 (55.7%) | |
A/G | 30 (38.0%) | 25 (31.6%) | |||
G/G | 10 (12.7%) | 10 (12.7%) | |||
0.6210301 | Del | 93 (58.9%) | 98 (62.0%) | ||
Ins | 65 (41.1%) | 60 (38.0%) | |||
HLA-G 14-bp | rs66554220 | Ins/Ins | 15 (19.0%) | 8 (10.1%) | |
Ins/Del | 35 (44.3%) | 44 (55.7%) | |||
Del/Del | 29 (36.7%) | 27 (34.2%) |
Genetic Model | Genotype | Patients (N = 79) | Control (N = 79) | OR (95% CI) | p Value | FDR |
---|---|---|---|---|---|---|
HLA-G 14-bp indel | ||||||
Codominant | DD | 29 (36.7%) | 27 (34.2%) | 1 | 0.196 | 0.440 |
DI | 35 (44.3%) | 44 (55.7%) | 0.74 (0.37–1.47) | - | ||
II | 15 (19.0%) | 8 (10.1%) | 1.75 (0.64–4.77) | - | ||
Dominant | DD | 29 (36.7%) | 27 (34.2%) | 1 | 0.739 | 0.8321 |
DI-II | 50 (63.3%) | 52 (65.8%) | 0.90 (0.47–1.72) | - | ||
Recessive | DD-II | 64 (81.0%) | 71 (89.9%) | 1 | 0.112 | 0.335 |
II | 15 (19.0%) | 8 (10.1%) | 2.08 (0.83–5.23) | - | ||
IL-17A -197G>A rs2275913 | ||||||
Codominant | GG | 50 (63.3%) | 56 (70.9%) | 1 | 0.075 | 0.335 |
GA | 20 (25.3%) | 21 (26.6%) | 1.07 (0.52–2.19) | - | ||
AA | 9 (11.4%) | 2 (2.5%) | 5.04 (1.04–24.44) | - | ||
Dominant | GG | 50 (63.3%) | 56 (70.9%) | 1 | 0.310 | 0.557 |
GA-AA | 29 (36.7%) | 23 (29.1%) | 1.41 (0.72–2.75) | - | ||
Recessive | GG-GA | 70 (88.6%) | 77 (97.5%) | 1 | 0.023 | 0.209 |
AA | 9 (11.4%) | 2 (2.5%) | 4.95 (1.03–23.69) | - | ||
IL-17RA -947A>G rs4819554 | ||||||
Codominant | AA | 39 (49.4%) | 44 (55.7%) | 1 | 0.685 | 0.832 |
AG | 30 (38.0%) | 25 (31.6%) | 1.35 (0.68–2.68) | - | ||
GG | 10 (12.7%) | 10 (12.7%) | 1.13 (0.42–3.00) | - | ||
Dominant | AA | 39 (49.4%) | 44 (55.7%) | 1 | 0.425 | 0.638 |
AG-GG | 40 (50.6%) | 35 (44.3%) | 1.29 (0.69–2.41) | - | ||
Recessive | AA-AG | 69 (87.3%) | 69 (87.3%) | 1 | 1.00 | 1.000 |
GG | 10 (12.7%) | 10 (12.7%) | 1.00 (0.39–2.55) | - |
Genetic Model | Genotype | Patients (N = 78) | Control (N = 78) | OR (95% CI) | p Value | FDR |
---|---|---|---|---|---|---|
HLA-G 14-bp indel | ||||||
Codominant | DD | 29 (37.2%) | 27 (34.6%) | 1 | 0.026 | 0.059 |
DI | 35 (44.9%) | 44 (55.1%) | 0.67 (0.28–1.61) | - | ||
II | 14 (17.9%) | 8 (10.0%) | 3.34 (0.98–11.41) | - | ||
Dominant | DD | 29 (37.2%) | 27 (34.6%) | 1 | 0.938 | 0.938 |
DI-II | 49 (62.8%) | 51 (65.4%) | 0.97 (0.43–2.16) | - | ||
Recessive | DD-II | 64 (82.1%) | 70 (89.7%) | 1 | 0.010 | 0.048 |
II | 14 (17.9%) | 8 (10.3%) | 4.20 (1.36–12.96) | - | ||
IL-17A -197G>A rs2275913 | ||||||
Codominant | GG | 50 (64.1%) | 55 (70.5%) | 1 | 0.021 | 0.059 |
GA | 19 (24.4%) | 21 (26.9%) | 1.22 (0.49–3.07) | - | ||
AA | 9 (11.5%) | 2 (2.6%) | 9.89 (1.63–59.92) | - | ||
Dominant | GG | 50 (64.1%) | 55 (70.5%) | 1 | 0.140 | 0.253 |
GA-AA | 28 (35.9%) | 23 (29.5%) | 1.86 (0.81–4.30) | - | ||
Recessive | GG-GA | 69 (88.5%) | 76 (97.4%) | 1 | 0.006 | 0.048 |
AA | 9 (11.5%) | 2 (2.6%) | 9.33 (1.57–55.38) | - | ||
IL-17RA -947A>G rs4819554 | ||||||
Codominant | AA | 38 (48.7%) | 43 (55.1%) | 1 | 0.733 | 0.825 |
AG | 30 (38.5%) | 25 (32.1%) | 0.86 (0.37–2.00) | - | ||
GG | 10 (12.8%) | 10 (12.8%) | 0.62 (0.18–2.09) | - | ||
Dominant | AA | 38 (48.7%) | 43 (55.1%) | 1 | 0.551 | 0.708 |
AG-GG | 40 (51.3%) | 35 (44.09) | 0.79 (0.36–1.73) | - | ||
Recessive | AA-AG | 68 (87.2%) | 68 (87.2%) | 1 | 0.484 | 0.708 |
GG | 10 (12.8%) | 10 (12.8%) | 0.66 (0.21–2.09) | - |
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de Souza, A.T.B.; Lucas, C.R.; de Carvalho, K.T.C.; Neta, A.P.R.; Bernardes-Oliveira, E.; Camargo, J.D.d.A.S.; Luchessi, A.D.; Cobucci, R.N.; Crispim, J.C.d.O. Homozygous AA Genotype of IL-17A and 14-bp Insertion Polymorphism in HLA-G 3′UTR Are Associated with Increased Risk of Gestational Diabetes Mellitus. Int. J. Environ. Res. Public Health 2025, 22, 327. https://doi.org/10.3390/ijerph22030327
de Souza ATB, Lucas CR, de Carvalho KTC, Neta APR, Bernardes-Oliveira E, Camargo JDdAS, Luchessi AD, Cobucci RN, Crispim JCdO. Homozygous AA Genotype of IL-17A and 14-bp Insertion Polymorphism in HLA-G 3′UTR Are Associated with Increased Risk of Gestational Diabetes Mellitus. International Journal of Environmental Research and Public Health. 2025; 22(3):327. https://doi.org/10.3390/ijerph22030327
Chicago/Turabian Stylede Souza, Amaxsell Thiago Barros, Cecília Rodrigues Lucas, Kleyton Thiago Costa de Carvalho, Antonia Pereira Rosa Neta, Emanuelly Bernardes-Oliveira, Juliana Dantas de Araújo Santos Camargo, André Ducati Luchessi, Ricardo Ney Cobucci, and Janaina Cristiana de Oliveira Crispim. 2025. "Homozygous AA Genotype of IL-17A and 14-bp Insertion Polymorphism in HLA-G 3′UTR Are Associated with Increased Risk of Gestational Diabetes Mellitus" International Journal of Environmental Research and Public Health 22, no. 3: 327. https://doi.org/10.3390/ijerph22030327
APA Stylede Souza, A. T. B., Lucas, C. R., de Carvalho, K. T. C., Neta, A. P. R., Bernardes-Oliveira, E., Camargo, J. D. d. A. S., Luchessi, A. D., Cobucci, R. N., & Crispim, J. C. d. O. (2025). Homozygous AA Genotype of IL-17A and 14-bp Insertion Polymorphism in HLA-G 3′UTR Are Associated with Increased Risk of Gestational Diabetes Mellitus. International Journal of Environmental Research and Public Health, 22(3), 327. https://doi.org/10.3390/ijerph22030327