Differential DNA methylation profile in infants born small-for-gestational-age: association with markers of adiposity and insulin resistance from birth to age 24 months

Marta Diaz; Edurne Garde; Abel Lopez-Bermejo; Francis de Zegher; Lourdes Ibañez

doi:10.1136/bmjdrc-2020-001402

Differential DNA methylation profile in infants born small-for-gestational-age: association with markers of adiposity and insulin resistance from birth to age 24 months

BMJ Open Diabetes Res Care. 2020 Oct;8(1):e001402. doi: 10.1136/bmjdrc-2020-001402.

Authors

Marta Diaz^{1

2}, Edurne Garde^{1

2}, Abel Lopez-Bermejo³, Francis de Zegher⁴, Lourdes Ibañez^{5

2}

Affiliations

¹ Endocrinology Department, Institut Pediàtric Hospital Sant Joan de Déu, University of Barcelona, Esplugues, Barcelona, Spain.
² Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain.
³ Department of Pediatrics, Dr. Josep Trueta Hospital and Girona Institute for Biomedical Research, Girona, Spain.
⁴ Department of Development & Regeneration, University of Leuven, Leuven, Flanders, Belgium.
⁵ Endocrinology Department, Institut Pediàtric Hospital Sant Joan de Déu, University of Barcelona, Esplugues, Barcelona, Spain libanez@hsjdbcn.org.

Abstract

Introduction: Prenatal growth restraint followed by rapid postnatal weight gain increases lifelong diabetes risk. Epigenetic dysregulation in critical windows could exert long-term effects on metabolism and confer such risk.

Research design and methods: We conducted a genome-wide DNA methylation profiling in peripheral blood from infants born appropriate-for-gestational-age (AGA, n=30) or small-for-gestational-age (SGA, n=21, with postnatal catch-up) at age 12 months, to identify new genes that may predispose to metabolic dysfunction. Candidate genes were validated by bisulfite pyrosequencing in the entire cohort. All infants were followed since birth; cord blood methylation profiling was previously reported. Endocrine-metabolic variables and body composition (dual-energy X-ray absorptiometry) were assessed at birth and at 12 and 24 months.

Results: GPR120 (cg14582356, cg01272400, cg23654127, cg03629447), NKX6.1 (cg22598426, cg07688460, cg17444738, cg12076463, cg10457539), CPT1A (cg14073497, cg00941258, cg12778395) and IGFBP 4 (cg15471812) genes were hypermethylated (GPR120, NKX6.1 were also hypermethylated in cord blood), whereas CHGA (cg13332653, cg15480367, cg05700406), FABP5 (cg00696973, cg10563714, cg16128701), CTRP1 (cg19231170, cg19472078, cg0164309, cg07162665, cg17758081, cg18996910, cg06709009), GAS6 (N/A), ONECUT1 (cg14217069, cg02061705, cg26158897, cg06657050, cg15446043) and SLC2A8 (cg20758474, cg19021975, cg11312566, cg12281690, cg04016166, cg03804985) genes were hypomethylated in SGA infants. These genes were related to β-cell development and function, inflammation, and glucose and lipid metabolism and associated with body mass index, body composition, and markers of insulin resistance at 12 and 24 months.

Conclusion: In conclusion, at 12 months, abnormal methylation of GPR120 and NKX6.1 persists and new epigenetic marks further involved in adipogenesis and energy homeostasis arise in SGA infants. These abnormalities may contribute to metabolic dysfunction and diabetes risk later in life.

Keywords: birth weight; body composition; insulin resistance; microarray analysis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adiposity / genetics
Child, Preschool
DNA Methylation / genetics
Fatty Acid-Binding Proteins
Female
Gestational Age
Humans
Infant
Infant, Newborn
Infant, Small for Gestational Age
Insulin Resistance* / genetics
Pregnancy

Substances

FABP5 protein, human
Fatty Acid-Binding Proteins