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      rs10732516 polymorphism at the IGF2/H19 locus associates with genotype-specific effects on placental DNA methylation and birth weight of newborns conceived by assisted reproductive technology

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          Abstract

          Background

          Assisted reproductive technology (ART) has been associated with low birth weight of fresh embryo transfer (FRESH) derived and increased birth weight of frozen embryo transfer (FET)-derived newborns. Owing to that, we focused on imprinted insulin-like growth factor 2 ( IGF2)/ H19 locus known to be important for normal growth. This locus is regulated by H19 imprinting control region (ICR) with seven binding sites for the methylation-sensitive zinc finger regulatory protein (CTCF). A polymorphism rs10732516 G/A in the sixth binding site for CTCF, associates with a genotype-specific trend to the DNA methylation. Due to this association, 62 couples with singleton pregnancies derived from FRESH (44 IVF/18 ICSI), 24 couples from FET (15 IVF/9 ICSI), and 157 couples with spontaneously conceived pregnancies as controls were recruited in Finland and Estonia for genotype-specific examination. DNA methylation levels at the H19 ICR, H19 DMR, and long interspersed nuclear elements in placental tissue were explored by MassARRAY EpiTYPER ( n = 122). Allele-specific changes in the methylation level of H19 ICR in placental tissue ( n = 26) and white blood cells (WBC, n = 8) were examined by bisulfite sequencing. Newborns’ ( n = 243) anthropometrics was analyzed by using international growth standards.

          Results

          A consistent trend of genotype-specific decreased methylation level was observed in paternal allele of rs10732516 paternal A/maternal G genotype, but not in paternal G/maternal A genotype, at H19 ICR in ART placentas. This hypomethylation was not detected in WBCs. Also genotype-specific differences in FRESH-derived newborns’ birth weight and head circumference were observed ( P = 0.04, P = 0.004, respectively): FRESH-derived newborns with G/G genotype were heavier ( P = 0.04) and had larger head circumference ( P = 0.002) compared to newborns with A/A genotype. Also, the placental weight and birth weight of controls, FRESH- and FET-derived newborns differed significantly in rs10732516 A/A genotype ( P = 0.024, P = 0.006, respectively): the placentas and newborns of FET-derived pregnancies were heavier compared to FRESH-derived pregnancies ( P = 0.02, P = 0.004, respectively).

          Conclusions

          The observed DNA methylation changes together with the phenotypic findings suggest that rs10732516 polymorphism associates with the effects of ART in a parent-of-origin manner. Therefore, this polymorphism should be considered when the effects of environmental factors on embryonic development are studied.

          Electronic supplementary material

          The online version of this article (10.1186/s13148-018-0511-2) contains supplementary material, which is available to authorized users.

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          Most cited references37

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          A global reference for human genetic variation

          The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.
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            Parental imprinting of the mouse insulin-like growth factor II gene.

            We are studying mice that carry a targeted disruption of the gene encoding insulin-like growth factor II (IGF-II). Transmission of this mutation through the male germline results in heterozygous progeny that are growth deficient. In contrast, when the disrupted gene is transmitted maternally, the heterozygous offspring are phenotypically normal. Therefore, the difference in growth phenotypes depends on the type of gamete contributing the mutated allele. Homozygous mutants are indistinguishable in appearance from growth-deficient heterozygous siblings. Nuclease protection and in situ hybridization analyses of the transcripts from the wild-type and mutated alleles indicate that only the paternal allele is expressed in embryos, while the maternal allele is silent. An exception is the choroid plexus and leptomeninges, where both alleles are transcriptionally active. These results demonstrate that IGF-II is indispensable for normal embryonic growth and that the IGF-II gene is subject to tissue-specific parental imprinting.
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              Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis.

              Earlier reviews have suggested that IVF/ICSI pregnancies are associated with higher risks. However, there have been recent advances in the way IVF/ICSI is done, leading to some controversy as to whether IVF/ICSI singletons are associated with higher perinatal risks. The objective of this systematic review was to provide an up-to-date comparison of obstetric and perinatal outcomes of the singletons born after IVF/ICSI and compare them with those of spontaneous conceptions. Extensive searches were done by two authors. The protocol was agreed a priori. PRISMA guidance was followed. The data were extracted in 2 × 2 tables. Risk ratio and risk difference were calculated on pooled data using Rev Man 5.1. Quality assessment of studies was performed using Critical Appraisal Skills programme. Sensitivity analysis was performed when the heterogeneity was high (I(2) > 50%). There were 20 matched cohort studies and 10 unmatched cohort studies included in this review. IVF/ICSI singleton pregnancies were associated with a higher risk (95% confidence interval) of ante-partum haemorrhage (2.49, 2.30-2.69), congenital anomalies (1.67, 1.33-2.09), hypertensive disorders of pregnancy (1.49, 1.39-1.59), preterm rupture of membranes (1.16, 1.07-1.26), Caesarean section (1.56, 1.51-1.60), low birthweight (1.65, 1.56-1.75), perinatal mortality (1.87, 1.48-2.37), preterm delivery (1.54, 1.47-1.62), gestational diabetes (1.48, 1.33-1.66), induction of labour (1.18, 1.10-1.28) and small for gestational age (1.39, 1.27-1.53). Singletons pregnancies after IVF/ICSI are associated with higher risks of obstetric and perinatal complications when compared with spontaneous conception. Further research is needed to determine which aspect of assisted reproduction technology poses most risk and how this risk can be minimized.
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                Author and article information

                Contributors
                heidi.marjonen@helsinki.fi
                pauliina.auvinen@helsinki.fi
                hanna.kahila@hus.fi
                olga.tsuiko@gmail.com
                sulev.koks@ut.ee
                airi.tiirats@kliinikum.ee
                triinviltrop@gmail.com
                viveca.soderstrom-anttila@hus.fi
                annemariasuikkari@gmail.com
                andres.salumets@ccht.ee
                aila.tiitinen@hus.fi
                nina.kaminen@helsinki.fi
                Journal
                Clin Epigenetics
                Clin Epigenetics
                Clinical Epigenetics
                BioMed Central (London )
                1868-7075
                1868-7083
                18 June 2018
                18 June 2018
                2018
                : 10
                : 80
                Affiliations
                [1 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Department of Medical and Clinical Genetics, Medicum, , University of Helsinki, ; Helsinki, Finland
                [2 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Department of Obstetrics and Gynecology, , University of Helsinki and Helsinki University Hospital, ; Helsinki, Finland
                [3 ]ISNI 0000 0001 0943 7661, GRID grid.10939.32, Department of Biomedicine, Institute of Biomedicine and Translational Medicine, , University of Tartu, ; Tartu, Estonia
                [4 ]GRID grid.487355.8, Competence Centre on Health Technologies, ; Tartu, Estonia
                [5 ]ISNI 0000 0001 0943 7661, GRID grid.10939.32, Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, , University of Tartu, ; Tartu, Estonia
                [6 ]ISNI 0000 0001 0671 1127, GRID grid.16697.3f, Department of Reproductive Biology, , Estonian University of Life Sciences, ; Tartu, Estonia
                [7 ]ISNI 0000 0001 0943 7661, GRID grid.10939.32, Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, , University of Tartu, ; Tartu, Estonia
                [8 ]ISNI 0000 0001 0585 7044, GRID grid.412269.a, Department of Paediatric ICU, , Tartu University Hospital, ; Tartu, Estonia
                [9 ]ISNI 0000 0001 1512 2412, GRID grid.460540.3, The Family Federation of Finland, Fertility Clinic, ; Helsinki, Finland
                Author information
                http://orcid.org/0000-0003-1255-4716
                Article
                511
                10.1186/s13148-018-0511-2
                6006593
                29946374
                c38eed18-756c-4963-b326-621b00961867
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 12 April 2018
                : 1 June 2018
                Funding
                Funded by: University of Helsinki, Faculty of Medicine
                Funded by: FundRef http://dx.doi.org/10.13039/100008376, Helsingin ja Uudenmaan Sairaanhoitopiiri;
                Funded by: Estonian Ministry of Education and Research
                Award ID: IUT34-16
                Award Recipient :
                Funded by: Enterprise Estonia
                Award ID: EU48695
                Award Recipient :
                Funded by: Horizon 2020 innovation program
                Award ID: WIDENLIFE, 692065
                Award Recipient :
                Funded by: European Union’s FP7 Marie Curie Industry-Academia Partnerships and Pathways funding
                Award ID: IAPP, SARM, EU324509
                Award Recipient :
                Funded by: MSCA-RISE-2015 project MOMENDO
                Award ID: 691058
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Genetics
                assisted reproductive technology,ivf,fresh embryo transfer,frozen embryo transfer,imprinting,igf2/h19,rs10732516,dna methylation,placenta,birth weight

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