Single-nucleotide polymorphisms in genes involved in folate metabolism or selected other metabolites and risk for gestational diabetes mellitus

doi:10.4239/wjd.v16.i5.103602

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May 15, 2025 (publication date) through Apr 25, 2025

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World Journal of Diabetes

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1948-9358

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Case Control Study

World J Diabetes. May 15, 2025; 16(5): 103602
Published online May 15, 2025. doi: 10.4239/wjd.v16.i5.103602

Table 1 General characteristics of the women in the case and control groups, n (%)

Characteristics	GDM¹	Control¹	χ²	P value
Characteristics	(n = 412)	(n = 412)	χ²	P value
Delivery age (years)			15.388	< 0.001
20-30	97 (23.6)	136 (33.0)
30-35	193 (47.0)	197 (47.8)
35-44	121 (29.4)	79 (19.2)
Pre-pregnancy BMI (kg/m²)			51.509	< 0.001
< 18.5	32 (8.3)	55 (13.3)
18.5-24.0	225 (63.9)	306 (85.7)
24.0-28.0	95 (27.0)	43 (12.0)
≥ 28.0	32 (8.3)	8 (1.9)
Ethnicity
Han	352 (91.4)	385 (93.4)	1.164	0.281
Other	33 (8.6)	27 (6.6)
Education level			2.89	0.089
College school and below	102 (26.5)	88 (21.4)
Bachelor degree and above	283 (73.5)	324 (78.6)
Per capita annual household income (RMB)	7.26		0.027
< 50000	74 (21.8)	58 (16.2)
50000-100000	151 (44.5)	146 (40.9)
≥ 100000	114 (33.6)	153 (42.9)
Primiparity			15.812	< 0.001
Yes	210 (55.6)	284 (69.3)
No	168 (44.4)	126 (30.7)
History of GDM			23.798	< 0.001
Yes	33 (8.0)	4 (1.0)
No	379 (92.0)	408 (99.0)
Family history of diabetes			3.195	0.074
Yes	59 (15.2)	45 (10.9)
No	329 (84.8)	366 (89.1)
Amount of exercise			2.614	0.271
No	174 (46.6)	167 (40.9)
Some	144 (38.6)	176 (43.1)
A large amount	55 (14.7)	65 (15.9)
Staple food habit (days a week)			1.152	0.562
7	164 (44.1)	177 (43.5)
3-6	186 (50.0)	198 (48.6)
0-2	22 (5.9)	32 (7.9)
Periconceptional folic acid supplementation (day)	3.06		0.216
≥ 45	85 (22.9)	83 (20.4)
15-44	51 (13.7)	74 (18.2)
< 15	235 (63.3)	250 (61.4)
Periconceptional multiple micronutrients containing folic acid supplementation (day)	0.381		0.827
≥ 45	102 (27.5)	104 (25.6)
15-44	78 (21.0)	87 (21.4)
< 15	191 (51.5)	216 (53.1)
Overview of folic acid supplementation (day)	0.406		0.816
≥ 45	165 (44.5)	172 (42.3)
15-44	89 (24.0)	100 (24.6)
< 15	117 (31.5)	135 (33.2)

¹Some sample data were missing. Missing data in the gestational diabetes mellitus group: Delivery age 1 case (0.24%); pre-pregnancy body mass index 28 cases (6.8%); ethnicity 27 cases (6.6%); education level 27 cases (6.6%); per capita annual household income 73 cases (17.7%); primiparity 34 cases (8.3%); family history of diabetes 24 cases (5.8%); amount of exercise 39 cases (9.5%); staple food habit 40 cases (9.7%); periconceptional folic acid supplementation 41 cases (10%); periconceptional multiple micronutrients containing folic acid supplementation 41 cases (10%); and overview of folic acid supplementation 41 cases (10%). Missing data in the control group: Per capita annual household income 55 cases (13.3%); primiparity 2 cases (0.5%); family history of diabetes 1 case (0.2%); amount of exercise 4 cases (1%); staple food habit 5 cases (1.2%); periconceptional folic acid supplementation 5 cases (1.2%); periconceptional multiple micronutrients containing folic acid supplementation 5 cases (1.2%); and overview of folic acid supplementation 5 cases (1.2%).

GDM: Gestational diabetes mellitus; BMI: Body mass index.

Table 2 Allele frequencies of single-nucleotide polymorphisms in the case and control groups, n (%)

Gene	SNP	Allele	GDM	Control	χ²	P value	P_adjusted¹
RFC-1	rs1051266	T	361 (44.0)	362 (44.1)	0.002	0.960	0.963
		C	459 (56.0)	458 (55.9)
MTHFR	rs1801131	G	116 (14.1)	129 (15.7)	0.810	0.368	0.694
		T	708 (85.9)	695 (84.3)
	rs1801133	G	364 (44.3)	378 (46.0)	0.481	0.488	0.694
		A	458 (55.7)	444 (54.0)
	rs2274976	T	46 (5.6)	54 (6.6)	0.661	0.416	0.694
		C	776 (94.4)	770 (93.4)
MTRR	rs1801394	G	217 (26.4)	202 (24.8)	0.581	0.446	0.694
		A	605 (73.6)	614 (75.2)
DHFR	rs408626	T	321 (39.1)	320 (38.8)	0.008	0.928	0.963
		C	501 (60.9)	504 (61.2)
MTR	rs1805087	G	69 (8.4)	85 (10.3)	1.791	0.181	0.542
		A	753 (91.6)	739 (89.7)
SHMT1	rs1979277	A	45 (5.5)	60 (7.3)	2.289	0.130	0.535
		G	779 (94.5)	764 (92.7)
GCP II	rs202676	G	282 (34.4)	253 (30.9)	2.333	0.127	0.535
		A	538 (65.6)	567 (69.1)
MTHFD1	rs2236225	A	193 (23.5)	196 (23.8)	0.014	0.905	0.963
		G	627 (76.5)	628 (76.2)
ADIPOQ	rs2241766	G	207 (25.2)	220 (26.7)	0.453	0.501	0.694
		T	613 (74.8)	604 (73.3)
	rs266729	G	213 (26.2)	212 (25.9)	0.030	0.862	0.963
		C	599 (73.8)	608 (74.1)
MTNR1B	rs10830963	G	389 (47.6)	317 (38.6)	13.517	< 0.001	0.004
		C	429 (52.4)	505 (61.4)
	rs1387153	T	368 (44.9)	322 (39.2)	5.484	0.019	0.173
		C	452 (55.1)	500 (60.8)
CDKAL1	rs7756992	A	395 (48.3)	396 (48.2)	0.002	0.963	0.963
CDKAL1		G	423 (51.7)	426 (51.8)
PPARG	rs1801282	G	53 (6.5)	65 (7.9)	1.253	0.263	0.676
		C	767 (93.5)	759 (92.1)
Chemerin	rs4721	G	367 (44.8)	387 (47.1)	0.893	0.345	0.694
		T	453 (55.2)	435 (52.9)
HHEX	rs5015480	C	156 (18.9)	133 (16.2)	2.087	0.149	0.535
	T	668 (81.1)	687 (83.8)

¹The P value was corrected using the Benjamini-Hochberg method.

SNP: Single-nucleotide polymorphism; GDM: Gestational diabetes mellitus.

Table 3 Gene-gene interaction models of 18 single-nucleotide polymorphisms and their association with gestational diabetes mellitus risk

Number of sites	The best model	Tr.BA¹	Te.BA²	P value	CVC³
1	rs10830963	0.5599	0.5599	0.055	10/10
2	rs10830963 rs4721	0.5999	0.5996	0.001	10/10
3	rs10830963 rs4721 rs1801131	0.6219	0.5490	0.172	5/10
4	rs10830963 rs4721 rs1801131 rs5015480	0.6587	0.5420	0.623	4/10
5	rs10830963 rs4721 rs1801131 rs5015480 rs7756992	0.7229	0.4798	0.828	2/10

¹Training Bal.Acc, training balanced accuracy, the accuracy in the training set, with a range of 0-1, where the larger the value, the higher the accuracy.

²Testing Bal.Acc, testing balanced accuracy, the accuracy in the testing set, with a range of 0-1, where the larger the value, the higher the accuracy.

³Cross-verifying consistency.

CVC: Cross-validation consistency.

Table 4 Gene-gene interaction model of 10 single-nucleotide polymorphisms related to folate metabolism enzymes on risk for gestational diabetes mellitus

Number of sites	The best model	Tr.BA¹	Te.BA²	P value	CVC³
1	rs202676	0.5338	0.5016	0.172	8/10
2	rs1801133 rs408626	0.5599	0.5015	0.623	7/10
3	rs1801133 rs408626 rs202676	0.5874	0.4955	0.623	6/10
4	rs1801133 rs408626 rs202676 rs1801394	0.6339	0.5568	0.172	9/10
5	rs1801133 rs408626 rs202676 rs1801394 rs1051266	0.6935	0.5053	0.623	10/10

¹Training Bal.Acc, training balanced accuracy, the accuracy in the training set, with a range of 0-1, where the larger the value, the higher the accuracy.

²Testing Bal.Acc, testing balanced accuracy, the accuracy in the testing set, with a range of 0-1, where the larger the value, the higher the accuracy.

³Cross-verifying consistency.

CVC: Cross-validation consistency.

Table 5 Gene-environment interaction model for gestational diabetes mellitus susceptibility

The best model	Tr.BA¹	Te.BA²	P value	CVC³
Pre-pregnancy BMI	0.6244	0.6242	0.001	10/10
Pre-pregnancy BMI rs10830963	0.6418	0.6235	0.001	9/10
Pre-pregnancy BMI rs10830963 per capita annual household income	0.6671	0.6331	0.001	6/10
Pre-pregnancy BMI rs10830963 per capita annual household income rs4721	0.7071	0.5777	0.001	5/10
Pre-pregnancy BMI delivery age per capita annual household income rs1801133 rs1387153	0.7756	0.5554	0.055	6/10

¹Training Bal.Acc, training balanced accuracy, the accuracy in the training set, with a range of 0-1, where the larger the value, the higher the accuracy.

²Testing Bal.Acc, testing balanced accuracy, the accuracy in the testing set, with a range of 0-1, where the larger the value, the higher the accuracy.

³Cross-verifying consistency.

CVC: Cross-validation consistency; BMI: Body mass index.

Citation: Zheng TT, Liu JH, Huang WT, Hong B, Wang D, Liu CY, Zhang J, Li SS, Wu SW, Wang Q, Chen L, Jin L. Single-nucleotide polymorphisms in genes involved in folate metabolism or selected other metabolites and risk for gestational diabetes mellitus. World J Diabetes 2025; 16(5): 103602
URL: https://www.wjgnet.com/1948-9358/full/v16/i5/103602.htm
DOI: https://dx.doi.org/10.4239/wjd.v16.i5.103602