rs10732516 polymorphism at the IGF2/H19 locus associates with a genotype-specific trend in placental DNA methylation and head circumference of prenatally alcohol-exposed newborns

Heidi Marjonen, Hanna Kahila, Nina Kaminen-Ahola

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu


STUDY QUESTION: Does prenatal alcohol exposure (PAE) affect regulation of the insulin-like growth factor 2 (IGF2)/H19 locus in placenta
and the growth-restricted phenotype of newborns?
SUMMARY ANSWER: PAE results in genotype-specific trends in both placental DNA methylation at the IGF2/H19 locus and head circumference
(HC) of newborns.
WHAT IS KNOWN ALREADY: PAE can disturb development of the nervous system and lead to restricted growth of the head, even
microcephaly. To clarify the etiology of alcohol-induced growth restriction, we focused on the imprinted IGF2/H19 locus known to be
important for normal placental and embryonic growth. The expression of IGF2 and a negative growth controller H19 are regulated by the
H19 imprinting control region (H19 ICR) with seven-binding sites for the methylation-sensitive zinc-finger regulatory protein CTCF. A single
nucleotide polymorphism rs10732516 G/A in the sixth-binding site has shown to associate with genotype-specific DNA methylation profiles
at the H19 ICR.
STUDY DESIGN, SIZE, DURATION: By grouping 39 alcohol-exposed and 100 control samples according to rs10732516 polymorphism
we explored alcohol-induced, genotype-specific changes in DNA methylation at the H19 ICR and the promoter region of H19 (H19 differentially
methylated region). Also, IGF2 and H19 mRNA expression level in placenta as well as the phenotypes of newborns were examined.
PARTICIPANTS/MATERIALS, SETTING, METHODS: We explored alcohol-induced, genotype-specific changes in placental DNA
methylation by MassARRAY EpiTYPER and allele-specific changes by bisulphite sequencing. IGF2 and H19 expression in placenta were analyzed
by quantitative PCR and the HC, birthweight and birth length of newborns were examined using national growth charts.
MAIN RESULTS AND THE ROLE OF CHANCE: We observed a consistent trend in genotype-specific changes in DNA methylation at
H19 ICR in alcohol-exposed placentas. DNA methylation level in the normally highly methylated paternal allele of rs10732516 paternal A/
maternal G genotype was decreased in alcohol-exposed placentas. In addition to decreased IGF2 mRNA expression in alcohol-exposed placentas
of this specific genotype (P = 0.03), we observed significantly increased expression of H19 in relation to IGF2 when comparing all
alcohol-exposed placentas to unexposed controls (P = 0.006). Furthermore, phenotypic examination showed a significant genotype-specific
association between the alcohol exposure and HC of newborns (P = 0.001).
LehtiHuman reproduction open
DOI - pysyväislinkit
TilaJulkaistu - 5 lokakuuta 2017
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu


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