Integrative network analysis of differentially methylated regions to study the impact of gestational weight gain on maternal metabolism and fetal-neonatal growth

Argentato, Perla Pizzi; Guerra, João Victor da Silva; Luzia, Liania Alves; Ramos, Ester Silveira; Maschietto, Mariana; Rondó, Patrícia Helen de Carvalho

doi:10.1590/1678-4685-GMB-2023-0203

person Perla Pizzi Argentato

designed the research · participated in the collection of clinical data and biological material · performed the acquisition, analysis, and interpretation of DNA methylation data · directed statistical analysis · wrote the first draft of the manuscript · read and approved the final manuscript

schoolUniversidade de São Paulo, Faculdade de Saúde Pública, Departamento de Nutrição, São Paulo, SP, Brazil.

0000-0003-4625-1158

person João Victor da Silva Guerra

designed the research · conducted bioinformatics analysis · wrote the first draft of the manuscript · read and approved the final manuscript

schoolCentro Nacional de Pesquisa em Energia e Materiais (CNPEM), Laboratório Nacional de Biociências (LNBio). Campinas, SP, Brazil.schoolUniversidade Estadual de Campinas, Faculdade de Ciências Farmacêuticas, Programa de Pós-Graduação em Ciências Farmacêuticas, Campinas, SP, Brazil.

0000-0002-6800-4425

person Liania Alves Luzia

coordinated the fieldwork · performed the acquisition, analysis, and interpretation of DNA methylation data · reviewed the manuscript and provided critical revision · read and approved the final manuscript

schoolUniversidade de São Paulo, Faculdade de Saúde Pública, Departamento de Nutrição, São Paulo, SP, Brazil.

0000-0001-8317-1398

person Ester Silveira Ramos

designed the research · performed the acquisition, analysis, and interpretation of DNA methylation data · reviewed the manuscript and provided critical revision · read and approved the final manuscript

schoolUniversidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Genética, Ribeirão Preto, SP, Brazil.

0000-0001-7253-2143

person Mariana Maschietto

designed the research · conducted bioinformatics analysis · reviewed the manuscript and provided critical revision · read and approved the final manuscript

schoolUniversidade Estadual de Campinas, Instituto de Biologia, Departamento de Biologia Estrutural e Funcional, Campinas, SP, Brazil.schoolCentro Infantil Boldrini, Campinas, SP, Brazil.

0000-0003-2589-3186

person Patrícia Helen de Carvalho Rondó

designed the research · coordinated the fieldwork · directed statistical analysis · reviewed the manuscript and provided critical revision · read and approved the final manuscript

schoolUniversidade de São Paulo, Faculdade de Saúde Pública, Departamento de Nutrição, São Paulo, SP, Brazil.

0000-0002-8308-6393

personSend correspondence to Patrícia Helen de Carvalho Rondó. Universidade de São Paulo, Faculdade de Saúde Pública, Departamento de Nutrição, Avenida Dr Arnaldo, 715, 01246-904, São Paulo, SP, Brazil. E-mail:
phcrondo@usp.br.

Associate Editor:

Regina C. Mingroni-Netto

Conflict of Interest

The authors declare that there is no conflict of interest that could be perceived as prejudicial to the impartiality of the reported research.

Variables	Excessive gestational weight gain (n= 30)	Adequate gestational weight gain (n= 45)	p
Pregnant women
Biochemical parameters
T1 Fasting blood sugar (mg/dL)	77.93±6.26	79.60±6.97	0.410
T2 Fasting blood sugar (mg/dL)	75.67±7.21	75.62±8.02	0.394
T3 Fasting blood sugar (mg/dL)	75.52±8.17	75.53±6.46	0.149
T1 Fasting insulin (uUI/mL)	6.40±3.56	6.98±4.27	0.718
T2 Fasting insulin (uUI/mL)	7.77±3.36	6.76±3.75	0.118
T3 Fasting insulin (uUI/mL)	10.97±5.56	9.56±6.01	0.199
T1 Total cholesterol (mg/dL)	169.10±31.21	175.38±24.87	0.106
T2 Total cholesterol (mg/dL)	220.27±32.45	219.87±47.77	0.014
T3 Total cholesterol (mg/dL)	235.66±55.15	245.82±41.74	0.408
T1 Triglycerides (mg/dL)	103.63±31.00	99.76±35.05	0.452
T2 Triglycerides (mg/dL)	161.50±39.30	143.29±51.58	0.030
T3 Triglycerides (mg/dL)	195.14±61.01	196.67±57.68	0.965
T1 Ultra-sensitive C-reactive protein (mg/dL)	6.98±8.54	5.60±5.74	0.129
T2 Ultra-sensitive C-reactive protein (mg/dL)	6.41±6.81	8.26±12.06	0.710
T3 Ultra-sensitive C-reactive protein (mg/dL)	6.35±8.22	7.06±9.91	0.658
Fetus
Biometric measurements
T2 Biparietal diameter (cm)	5.92±0.67	5.82±0.68	0.846
T3 Biparietal diameter (cm)	8.48±0.48	8.47±0.52	0.653
T2 Occipito-frontal diameter (cm)	7.48±0.76	7.44±0.81	0.423
T3 Occipito-frontal diameter (cm)	10.50±0.51	10.71±0.85	0.005
T2 Head circumference (cm)	21.20±2.16	21.23±2.91	0.978
T3 Head circumference (cm)	29.97±1.39	29.93±3.79	0.099
T2 Abdominal circumference (cm)	18.44±2.20	18.46±2.41	0.508
T3 Abdominal circumference (cm)	28.34±1.78	28.79±2.25	0.176
T2 Femur length (cm)	4.10±0.63	4.03±0.58	0.897
T3 Femur length (cm)	6.28±0.40	6.27±0.44	0.770
T2 Humeral length (cm)	3.87±0.53	3.77±0.45	0.338
T3 Humeral length (cm)	5.52±0.39	5.56±0.42	0.283
T2 Length (cm)	28.71±4.35	28.14±4.19	0.938
T3 Length (cm)	43.90±2.81	43.77±3.26	0.928
Neonate
Anthropometry
T4 Weight (g)	3502.50±292.45	3213.00±418.33	0.109
T4 Length (cm)	50.03±1.78	48.80±2.33	0.182
T4 Head circumference (cm)	34.57±1.30	33.68±1.44	0.016
T4 Thoracic perimeter (cm)	33.98±1.55	33.12±1.64	0.020
T4 Abdominal circumference (cm)	32.58±1.94	30.89±2.38	0.256

	Β	r²	p	95% CI
T3 Abdominal circumference
DMR 3	-24.266	0.679	0.006	-39.724; -8.808
Pre-pregnancy BMI	0.420		0.178	-0.231; 1.071
Gestational weight gain	0.152		0.043	0.006; 0.297
Maternal age	-0.039		0.561	-0.186; 0.107
Neonate sex	-0.016		0.976	-1.198; 1.165
Gestational age	0.658		0.118	-0.202; 1.518
DMR 5	-21.559	0.653	0.009	-36.275; -6.842
Pre-pregnancy BMI	0.492		0.151	-0.216; 1.201
Gestational weight gain	0.081		0.239	-0.064; 0.225
Maternal age	-0.034		0.626	-0.186; 0.118
Neonate sex	0.896		0.167	-0.451; 2.242
Gestational age	1.026		0.035	0.090; 1.962
DMR 9	-25.473	0.518	0.046	-50.323; -0.624
Pre-pregnancy BMI	-0.141		0.658	-0.836; 0.555
Gestational weight gain	0.131		0.127	-0.045; 0.308
Maternal age	0.011		0.890	-0.169; 0.192
Neonate sex	0.732		0.321	-0.846; 2.311
Gestational age	0.439		0.377	-0.629; 1.507
T3 Head circumference
DMR 5	-4.786	0.961	0.001	-6.136; -3.435
Pre-pregnancy BMI	0.090		0.012	0.025; 0.155
Gestational weight gain	0.026		0.002	0.013; 0.039
Maternal age	0.005		0.467	-0.009; 0.019
Neonate sex	0.175		0.011	0.051; 0.298
Gestational age	0.341		0.000	0.255; 0.427
T4 Head circumference
DMR 1	7.852	0.730	0.023	1.369; 14.335
Pre-pregnancy BMI	0.425		0.081	-0.065; 0.915
Gestational weight gain	0.112		0.050	0.000; 0.225
Maternal age	-0.036		0.358	-0.121; 0.048
Neonate sex	0.267		0.521	-0.637; 1.171
Gestational age	0.322		0.058	-0.013; 0.656
T2 Fasting insulin
DMR 2	-20.210	0.903	0.001	-28.229; -12.191
Pre-pregnancy BMI	0.669		0.023	0.118; 1.220
Gestational weight gain	0.395		0.000	0.258; 0.532
Maternal age	0.188		0.017	0.043; 0.334
Neonate sex	-2.305		0.006	-3.750; -0.860
Gestational age	-0.659		0.015	-1.154; -0.165
DMR 6	-45.581	0.804	0.008	-75.799; -15.363
Pre-pregnancy BMI	0.665		0.092	-0.131; 1.461
Gestational weight gain	0.522		0.001	0.288; 0.756
Maternal age	0.177		0.083	-0.029; 0.383
Neonate sex	-2.888		0.015	-5.058; -0.718
Gestational age	-0.876		0.026	-1.620; -0.132
T1 Triglycerides
DMR2	-245.651	0.608	0.034	-468.802; -22.501
Pre-pregnancy BMI	6.646		0.353	-8.701; 21.993
Gestational weight gain	3.540		0.087	-0.635; 7.715
Maternal age	1.229		0.401	-1.926; 4.384
Neonate sex	-22.645		0.153	-55.468; 10.178
Gestational age	3.890		0.523	-9.357; 17.136
T2 Triglycerides
DMR 2	-250.430	0.761	0.029	-469.322; -31.538
Pre-pregnancy BMI	19.867		0.015	4.829; 34.906
Gestational weight gain	4.418		0.025	0.680; 8.157
Maternal age	1.808		0.330	-2.164; 5.781
Neonate sex	-30.450		0.115	-69.882; 8.983
Gestational age	1.135		0.853	-12.372; 14.643
T3 Triglycerides
DMR 9	-1468.914	0.804	0.001	-2126.408; -1.419
Pre-pregnancy BMI	12.552		0.157	-5.846; 30.951
Gestational weight gain	4.693		0.049	0.017; 9.369
Maternal age	2.469		0.271	-2.299; 7.237
Neonate sex	3.075		0.871	-38.696; 44.846
Gestational age	-9.943		0.447	-38.205; 18.319

[TFN1] Mean±SD. T test for independent samples. BMI: Body Mass Index. T1 = ≤ 15 gestational weeks. T2 = 20-26 weeks. T3 = 30-36 weeks and T4 = delivery.