ORIGINAL PAPER / OBSTETRICS

IL16 and IL18 gene polymorphisms in women with gestational diabetes

Maciej Tarnowski1, Alicja Wieczorek2, Violetta Dziedziejko3, Krzysztof Safranow3, Przemysław Ustianowski4, Zbigniew Celewicz4, Andrzej Pawlik1

1Department of Physiology, Pomeranian Medical University, Szczecin, Poland
2”For-Dent” Medical Center, Pyrzyce, Poland
3Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin, Poland
4Department of Perinatology, Obstetrics and Gynecology, Pomeranian Medical University, Szczecin, Poland

Corresponding author:

Andrzej Pawlik

Department of Physiology, Pomeranian Medical University

Powstancow Wlkp. 72, 70–111 Szczecin, Poland

tel.: +48 91 466 16 11, fax: +48 91 466 16 12

e-mail: pawand@poczta.onet.pl

ABSTRACT

Objectives: Gestational diabetes mellitus is a carbohydrate intolerance that occurs during pregnancy. Various inflammatory mediators are considered to be risk factors leading to GDM development. Among them are pro-inflammatory cytokines, such as IL16 and IL18. The aim of this study was to examine the association between IL16 and IL18 polymorphisms and GDM.

Material and methods: This study included 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance (NGT). All samples were genotyped in duplicate using allelic discrimination assays with TaqMan® probes.

Results: We observed that there was a decreased frequency of IL16 rs4778889 CC genotype carriers among women with GDM (CC vs. CT + TT: OR = 0.14; 95% CI = 0.02–1.15; p = 0.034). However, there was no significant difference in the distribution of alleles (C vs. T: OR = 0.81; 95% CI = 0.54–1.21; p = 0.30). There was a decreased frequency of the IL18 rs187238 G allele among GDM women (G vs. C: OR = 0.71; 95% CI = 0.53–0.96; p = 0.027). We also observed a decreased frequency of the IL18 rs1946518 T allele among women with GDM; however, this difference had only borderline statistical significance. We observed an association between IL18 rs187238, rs1946518 and BMI in pregnant women.

Conclusions: The results of this study suggest that IL18 rs187238 and rs1946518 polymorphisms may be associated with an increased risk of GDM as well as with BMI in pregnant women.

Key words: polymorphism, SNP, gestational diabetes, genes, metabolism

Ginekologia Polska 2017; 88, 5: 249–254

INTRODUCTION

Gestational diabetes mellitus (GDM) is a carbohydrate intolerance caused by decreased insulin synthesis and action, which is diagnosed in the second or third trimester of pregnancy. The important risk factors of GDM include advanced maternal age, obesity and a family history of type 2 diabetes (T2DM) [1, 2]. This disorder is associated with several maternal and neonatal metabolic and cardiovascular complications [3, 4]. Recent studies suggest that genetic factors play important role in pathogenesis of GDM [5]. The role of the inflammatory response in the pathogenesis of GDM has been recently investigated [6]. Various inflammatory mediators are considered to be risk factors leading to GDM development [7, 8], including cytokines. Cytokines are a group of proteins produced by cells involved in the immune response, and they act as immune regulators and mediators. Cytokines may perform both pro-inflammatory as well as anti-inflammatory actions. Diabetes, carbohydrate intolerance and insulin resistance are associated with an increased synthesis of pro-inflammatory cytokines, such as IL16 and IL18 [9]. Recent studies suggest that pro-inflammatory cytokines also play an important role in GDM pathogenesis [10]. The inflammatory response and an imbalance between pro-inflammatory and anti-inflammatory cytokines may lead to the development of pregnancy-induced glucose intolerance and insulin resistance [11]. Previous studies have revealed that cytokine production may be associated with polymorphisms in cytokine-encoding genes [12]. These polymorphisms may alter gene expression and cytokine synthesis, and have been investigated in patients with type 1 and type 2 diabetes [13]. These polymorphisms may be associated with increased IL16 and IL18 synthesis in some patients and enhanced inflammatory response. Previous studies have shown that these polymorphisms may be associated with increased risk of inflammatory diseases [14]. The aim of this study was to examine the association between IL16 and IL18 gene polymorphisms and GDM.

MATERIAL AND METHODS

Patients

This study included 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance (NGT). The diagnosis of GDM was based on a 75 g oral glucose tolerance test (OGTT) at 24–28 weeks’ gestation, according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria [15]. The diagnosis of GDM was made when one of the following plasma glucose values in the OGTT was met or exceeded: fasting plasma glucose of 92 mg/dL (5.1 mmol/L); 1 h plasma glucose of 180 mg/dL (10.0 mmol/L); 2 h plasma glucose of 153 mg/dL (8.5 mmol/L) [15]. Exclusion criteria were: type 1 and type 2 diabetes, autoimmune and inflammatory diseases, neoplastic diseases and chronic infections. Among the pregnant women with GDM, 152 (75%) were treated with diet control alone throughout the pregnancy, whereas the remaining 52 (25%) were treated with diet control and insulin until delivery. The study was approved by the ethics committee in Pomeranian Medical University, Szczecin, Poland, and written informed consent was obtained from all subjects.

Methods

All samples were genotyped in duplicate using allelic discrimination assays with TaqMan® probes (Applied Bio- systems, Carlsbad, California, USA) on a Real-Time PCR Detection System (Applied Biosystems). To discriminate the IL16 rs4778889 and IL18 rs187238, rs1946518 gene polymorphisms, TaqMan® Pre-Designed SNP Genotyping Assays were used (the assay IDs were C__31837550_10, C___2408543_10 and C___2898460_10 respectively). Appropriate primers were included and fluorescently labelled (FAM and VIC) MGB™ probes were used to detect the alleles.

Statistical analysis

The agreement of the genotype distribution with the Hardy-Weinberg equilibrium (HWE) was assessed using the exact test. A chi-square test was used to compare genotype and allele distributions between groups. Clinical parame- ters were compared between genotype groups using the Mann-Whitney test. Statistical significance was assessed at the value of p < 0.05.

RESULTS

Clinical parameters of women with and without GDM are shown in Table 1. The family history of type 2 diabetes in women with GDM was noted in 82 cases (40%).

Table 1. Clinical parameters of women with and without GDM
Parameters	Control group N = 207	GDM group N = 204
	Mean ± SD	Mean ± SD
Age [years]	29.2 ± 5.0	31.7 ± 4.5
Height [cm]	165.5 ± 5.7	164.7 ± 5.9
Body mass before pregnancy [kg]	63.3 ± 12.4	68.3 ± 16.4
Body mass at birth [kg]	78.1 ± 14.2	79.5 ± 17.1
Body mass increase during pregnancy [kg]	14.8 ± 5.4	11.1 ± 5.2
BMI before pregnancy [kg/m2]	23.0 ± 4.0	25.1 ± 5.5
BMI at birth [kg/m2]	28.4 ± 4.5	29.3 ± 5.9
BMI increase during pregnancy [kg/m2]	5.4 ± 1.9	4.1 ± 2.0
Current number of pregnancy	1.8 ± 1.1	2.0 ± 1.0
HbA1c [%]	–	5.56 ± 0.48
Daily insulin requirement [unit]	–	5.28 ± 11.45
Childbirth [weeks]	39.1 ± 1.6	38.5 ± 1.9
Newborn body mass [g]	3362 ± 530	3265 ± 631
APGAR (0–10)	9.9 ± 0.4	9.7 ± 1.0
BMI — body mass index; HbA1c — glycated haemoglobin

The studied genotypes were distributed according to HWE and are shown in Table 2.

Table 2. Distribution of IL16 and IL18 genotypes and alleles in women with GDM and controls
	Control group		GDM		p value^		OR (95% CI)	p value^
	N	%	N	%
IL16 rs4778889 genotype
TT	153	73.91%	155	75.98%	0.11	CC + CT vs. TT	0.90 (0.57–1.40)	0.63
CT	47	22.71%	48	23.53%		CC vs. CT + TT	0.14 (0.02–1.15)	0.034
CC	7	3.38%	1	0.49%		CC vs. TT	0.14 (0.02–1.16)	0.035
						CT vs. TT	1.01 (0.64–1.60)	0.97
						CC vs. CT	0.14 (0.02–1.18)	0.039
Allele
T	353	85.27%	358	87.75%		C vs. T	0.81 (0.54–1.21)	0.30
C	61	14.73%	50	12.25%
IL18 rs187238 genotype
CC	94	45.41%	109	53.43%	0.069	GG + CG vs. CC	0.73 (0.49–1.07)	0.10
CG	86	41.55%	81	39.71%		GG vs. CG + CC	0.49 (0.25–0.97)	0.037
GG	27	13.04%	14	6.86%		GG vs. CC	0.45 (0.22–0.90)	0.022
						CG vs. CC	0.81 (0.54–1.22)	0.32
						GG vs. CG	0.55 (0.27–1.12)	0.098
Allele
C	274	66.18%	299	73.28%		G vs. C	0.71 (0.53–0.96)	0.027
G	140	33.82%	109	26.72%
IL18 rs1946518 genotype
GG	62	29.95%	73	35.78%	0.15	TT + GT vs. GG	0.77 (0.51–1.16)	0.21
GT	105	50.72%	105	51.47%		TT vs. GT + GG	0.61 (0.36–1.04)	0.069
TT	40	19.32%	26	12.75%		TT vs. GG	0.55 (0.30–1.00)	0.051
						GT vs. GG	0.85 (0.55–1.31)	0.46
						TT vs. GT	0.65 (0.37–1.14)	0.13
Allele
G	229	55.31%	251	61.52%		T vs. G	0.77 (0.59–1.02)	0.071
T	185	44.69%	157	38.48%
^χ2 test HWE: control group p = 0.17, GDM p = 0.32 for IL16 rs4778889 HWE: control group p = 0.35, GDM p = 1.00 for IL18 rs187238 HWE: control group p = 0.78, GDM p = 0.24 for IL18 rs1946518

We observed that there was a decreased frequency of IL16 rs4778889 CC genotype carriers among women with GDM (CC vs. CT + TT: OR = 0.14; 95% CI = 0.02–1.15; p = 0.034). However, there was no significant difference in the distribution of alleles (C vs. T: OR = 0.81; 95% CI = 0.54–1.21; p = 0.30).

Regarding the IL18 rs187238 polymorphism, there was a decreased frequency of the G allele among GDM women (G vs. C: OR = 0.71; 95% CI = 0.53–0.96; p = 0.027; GG vs. CG + CC: OR = 0.49; 95% CI = 0.25–0.97; p = 0.037). We also observed a decreased frequency of the IL18 rs1946518 T allele among women with GDM; however, this difference had only borderline statistical significance (T vs. G: OR = 0.77; 95% CI: 0.59–1.02; p = 0.071; Table 2).

Additionally, we examined the association between the studied genotypes and the following clinical parameters in women with GDM: body mass before pregnancy, body mass at birth, body mass increase during pregnancy, BMI (body mass index) before pregnancy, BMI at birth, BMI increase during pregnancy, glycated haemoglobin HbA1c, daily insulin requirement, duration of pregnancy, newborn body mass and Apgar score. Among women with the CT genotype IL16 rs4778889, we observed a lower increase of body mass and BMI during pregnancy compared with the TT genotype (Table 3). Women with the CG genotype IL18 rs187238 had a higher increase of body mass and BMI during pregnancy than the CC genotype (Table 4). Women with the GT genotype IL18 rs1946518 had a higher body mass and BMI before pregnancy and at birth compared with the GG genotype (Table 5).

Table 3. Clinical parameters of women with GDM stratified according to IL16 rs4778889 genotype
Parameters	IL16 rs4778889 genotype
	TT N = 155	CT N = 48	TT vs. CT
	Mean ± SD	Mean ± SD	p&
Body mass before pregnancy [kg]	69.0 ± 16.9	66.4 ± 14.6	0.36
Body mass at birth [kg]	80.6 ± 17.6	76.1 ± 15.2	0.091
Body mass increase during pregnancy [kg]	11.5 ± 5.3	9.8 ± 4.8	0.027
BMI before pregnancy [kg/m2]	25.4 ± 5.8	24.4 ± 4.8	0.31
BMI at birth [kg/m2]	29.7 ± 6.1	28.0 ± 5.1	0.053
BMI increase during pregnancy [kg/m2]	4.3 ± 2.0	3.6 ± 1.8	0.021
HbA1c [%]	5.56 ± 0.48	5.57 ± 0.45	0.99
Daily insulin requirement [unit]	5.07 ± 10.93	6.06 ± 13.17	0.97
Childbirth [weeks]	38.5 ± 1.8	38.4 ± 2.2	0.75
Newborn body mass [g]	3267 ± 627	3272 ± 649	0.90
APGAR (0–10)	9.7 ± 1.0	9.8 ± 1.0	0.41
&Mann-Whitney U test

Table 4. Clinical parameters of women with GDM stratified according to IL18 rs187238 genotype
Parameters	IL18 rs187238 genotype
	CC N = 109	CG N = 81	GG N = 14	CC vs. CG	CC vs. GG	CG vs. GG
	Mean ± SD	Mean ± SD	Mean ± SD	p&
Body mass before pregnancy [kg]	67.6 ± 15.9	70.2 ± 17.6	62.9 ± 12.1	0.27	0.31	0.11
Body mass at birth [kg]	78.3 ± 16.4	82.2 ± 18.5	72.8 ± 12.1	0.11	0.28	0.059
Body mass increase during pregnancy [kg]	10.6 ± 5.4	12.0 ± 5.1	9.9 ± 3.9	0.013	0.91	0.12
BMI before pregnancy [kg/m2]	24.9 ± 5.0	25.8 ± 6.2	23.6 ± 4.9	0.41	0.29	0.17
BMI at birth [kg/m2]	28.8 ± 5.4	30.2 ± 6.5	27.3 ± 5.0	0.23	0.30	0.12
BMI increase during pregnancy [kg/m2]	4.0 ± 2.1	4.4 ± 1.8	3.7 ± 1.5	0.019	0.94	0.14
HbA1c [%]	5.57 ± 0.45	5.59 ± 0.50	5.29 ± 0.51	0.61	0.051	0.049
Daily insulin requirement [unit]	5.17 ± 11.05	5.64 ± 12.09	4.07 ± 11.45	0.51	0.32	0.54
Childbirth [weeks]	38.3 ± 2.3	38.7 ± 1.2	38.9 ± 1.2	0.79	0.38	0.48
Newborn body mass [g]	3189 ± 713	3381 ± 505	3182 ± 527	0.094	0.56	0.14
APGAR (0–10)	9.6 ± 1.2	9.8 ± 0.6	10.0 ± 0.0	0.26	0.13	0.22
&Mann-Whitney U test

Table 5. Clinical parameters of women with GDM stratified according to IL18 rs1946518 genotype
Parameters	IL18 rs1946518 genotype
	GG N = 73	GT N = 105	TT N = 26	GG vs. GT	GG vs. TT	GT vs. TT
	Mean ± SD	Mean ± SD	Mean ± SD	p&
Body mass before pregnancy [kg]	65.8 ± 15.8	70.3 ± 17.2	67.5 ± 13.9	0.022	0.34	0.50
Body mass at birth [kg]	76.4 ± 16.4	81.7 ± 17.9	79.0 ± 14.8	0.015	0.32	0.54
Body mass increase during pregnancy [kg]	10.6 ± 5.0	11.4 ± 5.3	11.5 ± 5.7	0.25	0.36	0.91
BMI before pregnancy [kg/m2]	24.2 ± 4.8	25.8 ± 6.0	25.2 ± 5.4	0.049	0.41	0.64
BMI at birth [kg/m2]	28.1 ± 5.0	30.0 ± 6.4	29.5 ± 5.7	0.045	0.33	0.82
BMI increase during pregnancy [kg/m2]	3.9 ± 1.9	4.2 ± 2.0	4.3 ± 2.1	0.34	0.36	0.93
HbA1c [%]	5.56 ± 0.49	5.57 ± 0.45	5.49 ± 0.55	0.62	0.64	0.49
Daily insulin requirement [unit]	4.42 ± 10.33	5.97 ± 12.15	4.88 ± 11.80	0.53	0.71	0.44
Childbirth [weeks]	38.1 ± 2.5	38.7 ± 1.4	38.7 ± 1.3	0.36	0.40	0.81
Newborn body mass [g]	3154 ± 747	3344 ± 522	3258 ± 650	0.084	0.85	0.37
APGAR (0–10)	9.5 ± 1.2	9.8 ± 0.9	9.8 ± 0.7	0.11	0.51	0.66
& Mann-Whitney U test

In the multivariate logistic regression analysis, taking into account maternal age, BMI before pregnancy as well as IL18 rs1946518 and IL16 rs4778889 polymorphisms we examined the independent risk factors of GDM. In this analysis, older age and higher BMI before pregnancy were independent significant predictors of a higher risk of GDM, while higher number of IL18 rs1946518 T alleles was a protective factor against GDM (Table 6).

Table 6. Multivariate logistic regression analysis for presence of GDM as the dependent variable
Parameters	OR (95% CI)	p
Age [years]	1.11 (1.06–1.16)	0.0000034
BMI before pregnancy [kg/m2]	1.09 (1.04–1.15)	0.00018
IL18 rs1946518 (number of T alleles)	0.73 (0.54–1.00)	0.0499
IL16 rs4778889 (CC vs. CT+TT)	0.15 (0.018–1.27)	0.081

DISCUSSION

In this study we examined the associations between IL16 and IL18 gene polymorphisms and GDM. Our results have indicated decreased frequency of IL16 rs4778889 CC genotype among women with GDM, decreased frequency of the IL18 rs187238 G allele, as well as decreased frequency of the IL18 rs1946518 T allele; however, this difference had borderline statistical significance (p = 0.071). In the multivariate logistic regression analysis older age and higher BMI before pregnancy were independent significant predictors of a higher risk of GDM, while higher number of IL18 rs1946518 T alleles was a protective factor against GDM.

It has been shown that IL18 promoter gene polymorphisms rs187238 and rs1946518, may influence promoter activity and IL18 production [12, 16, 17]. Previous studies have indicated that IL16 and IL18 are pro-inflammatory cytokines involved in the pathogenesis of diabetes [13, 18–20]. The significant role of low-grade inflammation has been confirmed in type 2 diabetes. Due to the similarity between T2DM and GDM, and the association between T2DM and inflammation, it has been hypothesised that inflammation could also be implicated in the pathophysiology of GDM [6, 7]. Several studies have examined cytokine production in pregnant women and it has been shown that during pregnancy, the imbalance between the production of anti-inflammatory and pro-inflammatory cytokines may induce low-grade inflammation and insulin resistance [21].

Previous studies have indicated that women with GDM have increased plasma IL16 and IL18 levels. This increase in IL16 in pregnant women was found to be associated with pre-eclampsia and preterm birth [22–24]. Kuzmicki et al. have shown that the balance between circulating pro- and anti-inflammatory cytokines is impaired in patients with GDM. Increased IL18 levels were detected in women with GDM and correlated with maternal obesity [25]. Fatima et al. found that increased IL18 levels in women with GDM were correlated with low-grade inflammation and insulin resistance [26]. IL18 gene polymorphisms have been investigated among patients with type 1 and type 2 diabetes [27–31]. Several studies suggest that these polymorphisms may be associated with an increased risk of diabetes and its cardiovascular complications. These polymorphisms were also studied in patients with obesity and it has been found that IL18 gene polymorphisms may be associated with obesity and low-grade inflammation [32, 33]. In our study, we also observed the associations between IL18 rs187238 and rs1946518 gene polymorphisms and BMI in pregnant women.

CONCLUSIONS

The results of this study suggest that IL16 rs4778889, IL18 rs187238 and rs1946518 polymorphisms may affect the risk of GDM as well as BMI in pregnant women. However, this observation requires further investigation in women of other populations.

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