Polymorphisms in gene UGT1A1 modify the association of prenatal exposure to polycyclic aromatic hydrocarbons with congenital heart diseases risk

Figures & data

Table 1. Maternal and fetal characteristics among the study subjects.

Characteristic	Controls (n = 270)	Cases (n = 357)	p Value
Maternal characteristics
Maternal age (years)^a	29 (26, 32)	28 (25, 31)	.010
Gestational week (weeks)^a	23 (18, 25)	25 (23, 27)	<.001
Housing renovation^b, n (%)	52 (19.26)	79 (22.13)	.381
Factory or landfill nearby^b, n (%)	37 (13.70)	56 (15.69)	.489
Cooking at home^b, n (%)	122 (45.19)	203 (56.86)	.004
Parental smoking or ETS exposure^b, n (%)	155 (57.41)	223 (62.46)	.200
Maternal alcohol consumption^b, n (%)	8 (2.96)	6 (1.68)	.282
Folic acid supplements, n (%)	240 (88.89)	297 (83.19)	.044
Urinary 1-OHPG levels (μg/g Cr)^a	0.32 (0.06, 0.74)	0.42 (0.15, 0.88)	.006
Fetal characteristics (CHDs subgroups)
Septal defects, n (%)		235 (65.83)
Conotruncal heart defects, n (%)		160 (44.82)
Right-sided obstructive malformations, n (%)		114 (31.93)
Left-sided obstructive malformations, n (%)		72 (20.17)
Anomalous pulmonary venous return, n (%)		64 (17.93)
Other cardiac structural abnormalities, n (%)		102 (28.57)

ETS: environmental tobacco smoke.

^a Since distribution was skewed, Wilcoxon’s rank sum Z test was used, and interquartile ranges P50 (P25, P75) were described.

^b The exposure timeframe was from the 3 months before pregnancy to the first trimester.

Table 2. Association between maternal UGT1A1 polymorphisms and the risk of CHDs.

Genotype	Controls (n (%))	Cases (n (%))	aOR^a (95% CI)
rs3755319
AA	123 (45.56)	152 (42.58)	Ref.
A/C-C/C	147 (54.44)	205 (57.42)	1.12 (0.79, 1.58)
rs887829
CC	214 (79.26)	286 (80.11)	Ref.
C/T-T/T	56 (20.74)	71 (19.89)	0.98 (0.64, 1.50)
rs4148323
GG	193 (71.48)	263 (73.67)	Ref.
G/A-A/A	77 (28.52)	94 (26.33)	1.07 (0.73, 1.57)
rs6742078
GG	212 (78.52)	284 (79.55)	Ref.
G/T-T/T	58 (21.48)	73 (20.45)	0.94 (0.61, 1.44)
rs6717546^b
GG	117 (43.33)	143 (40.06)	Ref.
G/A-A/A	152 (56.30)	209 (58.54)	0.92 (0.66, 1.28)

aOR: adjusted odds ratio; CI: confidence interval.

^a Adjusted for maternal age, gestational week, housing renovation, proximity to factory or landfill, cooking at home, parental smoking or ETS exposure, maternal alcohol consumption, folic acid supplements.

^b Five cases and one control failed to be genotyped for UGT1A1 rs6717546.

Figure 1. The best GMDR model of interaction among UGT1A1 rs4148323 and PAHs. Note: The graph was generated by the GMDR software. In each cell, the left bar represents a positive score, and the right bar a negative score. The cell with dark shading represents an interaction resulting in a high risk of having congenital heart diseases fetuses (the absolute magnitude of the positive score > the absolute magnitude of the negative score). The cell with light shading represents an interaction resulting in a low risk of having congenital heart diseases fetuses (the absolute magnitude of the positive score < the absolute magnitude of the negative score). The genotypes for UGT1A1 rs4148323 include GG, GA, and AA. The levels of PAHs exposure were categorized into two groups (high and low exposure groups).

Table 3. Gene–gene and gene–PAHs exposure interaction models in CHDs obtained using the GMDR method.

Interaction models	TBA1	TBA2	CVC	p Value
Gene–gene interaction
SNP1 SNP5	0.5377	0.4487	7/10	.99
SNP1 SNP3 SNP5	0.5480	0.4314	7/10	1.00
SNP1 SNP3 SNP4 SNP5	0.5599	0.4260	10/10	1.00
SNP1 SNP2 SNP3 SNP4 SNP5	0.5605	0.4197	10/10	1.00
Gene–PAHs exposure interaction
SNP3 PAHs	0.5711	0.5698	10/10	.01
SNP3 SNP5 PAHs	0.5753	0.5308	4/10	.05
SNP1 SNP3 SNP5 PAHs	0.5944	0.5185	10/10	.38
SNP1 SNP3 SNP4 SNP5 PAHs	0.6060	0.4940	10/10	.38
SNP1 SNP2 SNP3 SNP4 SNP5 PAHs	0.6069	0.4908	10/10	.38

SNP1: rs3755319; SNP2: rs887829; SNP3: rs4148323; SNP4: rs6742078; SNP5: rs6717546; TBA1: training balanced accuracy; TBA2: testing balanced accuracy; CVC: cross-validation consistency.

Table 4. The interaction between maternal PAHs exposure and UGT1A1 rs4148323 influencing CHDs based on additive model.

rs4148323	PAHs exposure	Controls (n (%))	Cases (n (%))	aOR^a (95% CI)
G/G	Low	41 (15.19)	29 (8.12)	Ref.
	High	152 (56.30)	234 (65.55)	1.74 (0.98, 3.06)
G/A-A/A	Low	21 (7.78)	14 (3.92)	0.91 (0.37, 2.22)
	High	56 (20.74)	80 (22.41)	2.00 (1.06, 3.79)

aOR: adjusted odds ratio; CI: confidence interval.

^a Adjusted for maternal age, gestational week, housing renovation, proximity to factory or landfill, cooking at home, parental smoking or ETS exposure, maternal alcohol consumption, folic acid supplements.