Abstract
Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p < 0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p < 0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p = 0.001).
Highlights
Birth size is an important clinical parameter that can be used for determining the health of the newborn and is highly correlated with postpartum morbidity and complications during labour
Similar associations have been demonstrated for large for gestational age (LGA) newborns, displaying an increased susceptibility for obesity, hypertension and diabetes mellitus compared to appropriate for gestational age (AGA) newborns[6,14]
It has been proposed that the underlying mechanisms leading to the same metabolic diseases in adult life differ between small for gestational age (SGA) and LGA newborns[17,18]
Summary
Birth size is an important clinical parameter that can be used for determining the health of the newborn and is highly correlated with postpartum morbidity and complications during labour. Numerous studies have demonstrated that both SGA and LGA newborns are at an increased risk for disease in later life, highlighting the importance of these anthropometric measures as surrogate parameters of fetal programming[6,7,8,9]. Studies investigating correlations between global DNA methylation and birth weight so far were only performed using rather small sample sizes[30,31,32,33]. Newer variants of genome wide array approaches like the Illumina MethylationEPIC bead chip still exclude regions of potentially meaningful biological variation[38] More comprehensive methods such as whole genome bisulfite sequencing are not feasible yet for utilization with large sample sizes. LC-MS/MS is reported to be the most sensitive method for absolute methyl cytosine quantification and is considered the current gold standard[37]
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