Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns

Abstract

Leptin is an adipokine that acts in the central nervous system and regulates energy balance. Animal models and human observational studies have suggested that leptin surge in the perinatal period has a critical role in programming long-term risk of obesity. In utero exposure to maternal hyperglycemia has been associated with increased risk of obesity later in life. Epigenetic mechanisms are suspected to be involved in fetal programming of long term metabolic diseases. We investigated whether DNA methylation levels near LEP locus mediate the relation between maternal glycemia and neonatal leptin levels using the 2-step epigenetic Mendelian randomization approach. We used data and samples from up to 485 mother-child dyads from Gen3G, a large prospective population-based cohort. First, we built a genetic risk score to capture maternal glycemia based on 10 known glycemic genetic variants (GRS 10 ) and showed it was an adequate instrumental variable (b D 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE D 0.007; P D 7.8 £ 10 ¡11 ; N D 467). A higher GRS 10 was associated with lower methylation levels at cg12083122 located near LEP (b D ¡0.072 unit per additional risk allele; SE D 0.04; P D 0.05; N D 166). Direction and effect size of association between the instrumental variable GRS 10 and methylation at cg12083122 were consistent with the negative association we observed using measured maternal glycemia. Lower DNA methylation levels at cg12083122 were associated with higher cord blood leptin levels (b D ¡0.17 log of cord blood leptin per unit; SE D 0.07; P D 0.01; N D 170). Our study supports that maternal glycemia is part of causal pathways influencing offspring leptin epigenetic regulation.

Maternal pre‐pregnancy BMI downregulates neonatal cord blood LEP methylation

“…Our results did not demonstrate a direct association between decreased LEP methylation and increased neonatal cord blood leptin levels or adiposity measures, as reported by Allard and colleagues . Allard's cohort included women with gestational diabetes, and analyses demonstrated that a higher maternal glycaemia risk score was associated with decreased LEP methylation and higher cord blood leptin levels.…”

Epigenetics and obesity cardiomyopathy: From pathophysiology to prevention and management

“…It is believed that epigenetic mechanisms involving leptin surge during the perinatal period in response to maternal hyperglycemia plays a pivotal role for fetal programming of adult onset metabolic disorders including obesity. DNA methylation near the leptin gene locus seems to control the correlation between maternal glycemic levels and neonatal leptin with high cord blood levels of leptin associated with lower DNA methylation at cg12083122 (Allard et al, 2015).…”

Leptin resistance in obesity: An epigenetic landscape

“…Maternal glycaemia is part of causal pathways influencing offspring leptin epigenetic regulation [80]. Moreover, it was demonstrated that LEP promoter DNA methylation is influenced by perinatal factors including: maternal obesity, infant growth, genotype and gender in a tissuespecific manner [81].…”