IGF2 DNA methylation is a modulator of newborn’s fetal growth and development

Figures & data

Table 1. Women and newborns characteristics

	Number	Mean ± SD	Range
1st T Mother’s age (years)	50	28.6 ± 3.4	20.0–38.0
1st T body mass index (kg/m2)	50	24.7 ± 3.3	19.6–32.5
1st T fasting glucose (mmol/L)	50	4.3 ± 0.4	3.4–5.4
1st T fasting insulin (mU/L)	50	6.0 ± 3.6	1.0–16.7
1st T IGF2 concentration (ng/mL)	37	817 ± 104	628–996
2nd T IGF2 concentration (ng/mL)	39	800 ± 114	517–1093
3rd T IGF2 concentration (ng/mL)	41	954 ± 186	650–1522
2h post-OGTT glucose (mmol/L) at 2nd T^†	50	7.1 ± 1.4	3.8–8.8
Weight gain between 1st and 3rd T (% of initial weight)	46	18.0 ± 6.3	1.5–33.1
Birth weight (kg)	50	3.3 ± 0.48	2.1–4.2
Cord blood IGF2 concentration (ng/mL)	43	453 ± 101	255–725

1st T, first trimester of gestation (between weeks 11 and 14); 2nd T, second trimester of gestation (between weeks 24 and 28); 3rd T, third trimester of gestation (between weeks 36 and 37). ^†Only one women fulfilled the ADA criteria for gestational diabetes mellitus.³³

Table 2. Spearman rank correlation coefficient between circulating IGF2 concentration and mRNA levels and mothers’ and newborns’ body composition-related phenotypes

	3rd T IGF2 levels	Cord blood IGF2 levels	IGF2 mRNA levels (fetal side)
1st T body weight	-0.35*	0.10	-
2nd T body weight	-0.37*	0.22	-
3rd T body weight	-0.37*	0.21	-
1st T fat mass	-0.39*	-0.06	-
Newborn’s height	-0.31^†	0.42**	0.04
Newborn’s weight	-0.24	0.25	0.07
Placenta weight	-0.22	0.29^†	0.32*

T, trimester of pregnancy; mRNA, mRNA; ^†p < 0.1; *p < 0.05; **p < 0.01.

Table 3. Spearman rank correlation coefficient between circulating IGF2 concentration and maternal side placenta IGF2/H19 DNA methylation levels

	3rd T IGF2 levels	Cord blood IGF2 levels
IGF2-DMR2-mean	-0.37*	0.20
IGF2-A1-CpG1	0.05	0.37*
IGF2-A1-CpG2	0.13	0.06
IGF2-A1-CpG3	-0.05	0.28^†
IGF2-A2-CpG1	0.21	0.16
IGF2-A2-CpG2	-0.11	0.19
H19-DMR-mean	0.09	0.31*

^† p < 0.1; *p < 0.05. The correlations remained similar when third trimester of pregnancy IGF2 concentration was corrected for maternal weight at first trimester of pregnancy or rs2107425 maternal genotype and when cord blood IGF2 concentration was corrected for newborns’ height or rs2107425 maternal genotype.

Figure 1.IGF2/H19 gene locus (chromosome 11p15). Numbers in the diamond shapes report Spearman correlation coefficient between CpG sites (white diamonds) or linkage disequilibrium (LD) values (r²) between H19 SNPs (gray diamonds) as computed with Haploview 4.0. Mean and SD are shown for DNA methylation values.

Table 4. Spearman rank correlation coefficient between placenta IGF2/H19 DNA methylation levels and fetal growth and development markers

	Height	Head circumference	Thorax circumference	Weight	Placenta weight
Fetal side
IGF2-DMR2-mean	0.40**	0.32*	0.32*	0.44**	0.22
IGF2-A1-CpG1	0.23	0.30*	0.37**	0.19	0.03
IGF2-A1-CpG2	0.16	0.29*	0.32*	0.17	0.06
IGF2-A1-CpG3	0.13	0.06	0.26^†	0.06	0.06
IGF2-A2-CpG1	0.02	0.08	-0.01	0.05	-0.05
IGF2-A2-CpG2	0.21	0.41**	0.40**	0.34*	0.15
H19-DMR-mean	-0.06	0.19	0.04	0.01	0.03
Maternal side
IGF2-DMR2-mean	0.12	0.12	0.13	0.21	0.14
IGF2-A1-CpG1	0.08	0.16	0.32*	0.34*	0.46***
IGF2-A1-CpG2	-0.02	0.19	0.16	0.15	0.29*
IGF2-A1-CpG3	0.02	0.13	0.30*	0.32*	0.32*
IGF2-A2-CpG1	-0.18	-0.01	-0.23	-0.08	-0.01
IGF2-A2-CpG2	0.17	0.15	0.24^†	0.28*	0.15
H19-DMR-mean	0.14	0.08	0.10	0.11	0.10

Circ, circumference; †p < 0.1; *p < 0.05; **p < 0.01. The correlations remained similar when corrected for rs2107425 (maternal genotype).

Table 5. Association analyses between IGF2/H19 polymorphisms and newborn growth markers

	rs10732516 (maternal genotype)				p-value
	C/C (n = 9) Mean ± SE	C/T (n = 28) Mean ± SE		T/T (n = 13) Mean ± SE
Birth weight (kg)	3.29 ± 0.15	3.44 ± 0.09		3.02 ± 0.13	0.03
Birth height (cm)	49.3 ± 0.6	50.0 ± 0.4		48.2 ± 0.5	0.02
Head circumference (cm)	34.1 ± 0.5	34.6 ± 0.3		33.5 ± 0.5	0.16
Thorax circumference (cm)	32.7 ± 0.7	33.4 ± 0.4		32.0 ± 0.6	0.16
Placenta weight (g)	554 ± 35	580 ± 20		524 ± 29	0.29
	rs2107425 (maternal genotype)
	A/A and A/G (n = 28) Mean ± SE		G/G (n = 22) Mean ± SE
Birth weight (kg)	3.46 ± 0.08		3.09 ± 0.10		0.004
Birth height (cm)	50.0 ± 0.4		48.8 ± 0.4		0.04
Head circumference (cm)	34.7 ± 0.3		33.6 ± 0.4		0.03
Thorax circumference (cm)	33.4 ± 0.4		32.2 ± 0.5		0.06
Placenta weight (g)	584 ± 20		533 ± 22		0.10
	rs10732516 (newborn genotype)
	C/C (n = 12) mean ± SE	C/T (n = 20) mean ± SE		T/T (n = 18) mean ± SE
Birth weight (kg)	3.50 ± 0.14	3.15 ± 0.11		3.35 ± 0.11	0.12
Birth height (cm)	49.8 ± 0.6	48.8 ± 0.5		49.8 ± 0.5	0.26
Head circumference (cm)	34.4 ± 0.5	33.6 ± 0.4		34.8 ± 0.4	0.08
Thorax circumference (cm)	33.6 ± 0.6	31.9 ± 0.5		33.5 ± 0.5	0.03
Placenta weight (g)	579 ± 31	542 ± 25		569 ± 25	0.60

American Diabetes Association. Standards of medical care in diabetes--2006. Diabetes Care 2006; 29:Suppl 1 S4 - 42; PMID: 16373931

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