ESPE Abstracts (2018) 89 FC15.3

Methylation of the C19MC microRNA Locus in the Placenta: A Mechanism whereby Maternal Body Size Links to that of the Child

Silvia Xargay-Torrenta, Anna Prats-Puigb, Berta Mas-Paresa, Judit Bassolsa, Clive J Petryc, Michael Girardotd, Francis de Zeghere, Lourdes Ibañezf, David B Dungerc, Robert Feild & Abel Lopez-Bermejoa,g

aInstitut d’Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; bEscola Universitària de la Salut i l’Esport (EUSES), Girona, Spain; cUniversity of Cambridge, Cambridge, UK; dInstitut de Génétique Moléculaire de Montpellier, Montpellier, France; eUniversity of Leuven, Leuven, Belgium; fInstitut de Recerca Pediàtrica Sant Joan de Déu, Barcelona, Spain; gHospital Dr. Josep Trueta, Girona, Spain

Background: The C19MC locus microRNA gene cluster is imprinted in the placenta. Imprinted genes control prenatal development and placental functions, and are epigenetically regulated. The factors that affect the DNA methylation status of C19MC regulatory region are unknown, as is the impact of this differential methylation on the offspring’s body size.

Objectives: To study in humans 1) the association of placental C19MC DNA methylation levels with parental body size and with transmission of haplotypes for the rs55765443 SNP in C19MC, and 2) the link between C19MC methylation and the offspring’s body size and/or body composition at birth and in prepubertal childhood.

Study design: A cohort of 72 healthy pregnant women (information available from 63 fathers) was studied. Pre-gestational maternal weight, height, body-mass index and gestational weight gain were registered. At birth, placentas were collected, and the infants’ weight and length were assessed (gestational age 40±1 week; birth weight z-score 0.1±0.9). DNA methylation at the imprinting control region (ICR) of C19MC (hg38 chr19:53648001-53648160) was quantified in placentas by bisulfite pyrosequencing. Genotyping of the rs55765443 SNP was performed for both parents in leukocytes, and for the infants in placental tissue, using restriction fragment length polymorphisms. The children’s body size and body composition were assessed at age 6 years.

Results: Less methylation in the placental C19MC ICR associated independently with larger body size of mother and child, more specifically with higher pre-gestational and pre-delivery weight and height of the mother (β=−0.307, P=0.011, R2=0.05; β=−0.371, P=0.003, R2=0.10; and β=−0.294, P=0.019, R2=0.04 respectively), and with higher weight (β=−0.552, P=0.003, R2=0.44), height (β=−0.486, P=0.009, R2=0.39), waist (β=−0.497, P=0.003, R2=0.33), hip (β=−0.449, P=0.004, R2=0.41) and fat mass (β=−0.428, P=0.004, R2=0.56) in the child. Parental transmission of the G or T alleles for rs55765443 did not significantly affect the methylation status of placental C19MC ICR.

Conclusions: Methylation of the C19MC locus in the placenta may be a transient, primate-specific, epigenetic mechanism whereby the father can link the body size of the mother to that of their future child.