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Altered DNA Methylation in Children Born to Mothers with Rheumatoid

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Altered DNA Methylation in Children Born to Mothers with Rheumatoid Rheumatoid arthritis Ann Rheum Dis: first published as 10.1136/annrheumdis-2018-214930 on 29 May 2019. Downloaded from EPIDEMIOLOGICAL SCIENCE Altered DNA methylation in children born to mothers with rheumatoid arthritis during pregnancy Hilal Ince-Askan, 1 Pooja R Mandaviya,2 Janine F Felix,3,4,5 Liesbeth Duijts,3,6,7 Joyce B van Meurs,2 Johanna M W Hazes,1 Radboud J E M Dolhain1 Handling editor Josef S ABSTRACT Key messages Smolen Objectives The main objective of this study was to determine whether the DNA methylation profile of ► Additional material is What is already known about this subject? published online only. To children born to mothers with rheumatoid arthritis (RA) is ► Adverse exposures in early life are associated view please visit the journal different from that of children born to mothers from the with later-life health. online (http:// dx. doi. org/ 10. general population. In addition, we aimed to determine Epigenetic changes are thought to be one of the 1136annrheumdis- 2018- whether any differences in methylation are associated ► 214930). underlying mechanisms. with maternal RA disease activity or medication use There is not much known about the during pregnancy. ► For numbered affiliations see consequences of maternal rheumatoid arthritis end of article. Methods For this study, genome-wide DNA (RA) on the offsprings’ long-term health. methylation was measured at cytosine-phosphate- Correspondence to guanine (CpG) sites, using the Infinium Illumina What does this study add? Hilal Ince-Askan, Rheumatology, HumanMethylation 450K BeadChip, in 80 blood samples Erasmus Medical Centre, ► DNA methylation is different in children born to from children (mean age=6.8 years) born to mothers Rotterdam 3000 CA, The mothers with RA compared with mothers from Netherlands; with RA. As controls, blood samples from 354 children the general population. h. ince- askan@ erasmusmc. nl (mean age=6.0 years) from the population-based Generation R Study were used. Linear mixed models Received 16 December 2018 How might this impact on clinical practice or were performed to investigate differential methylation Revised 17 April 2019 future developments? Accepted 7 May 2019 between the groups, corrected for relevant confounders. ► Maternal RA disease during pregnancy might Published Online First Results A total of 147 CpGs were differentially have lifelong consequences for the offspring. 29 May 2019 methylated between blood samples of children born ► More research in this particular field must be to mothers with RA and the control blood samples. undertaken. The five most significantly associated CpGs were cg06642177, cg08867893, cg06778273, cg07786668 and cg20116574. The differences in methylation were gene expression depends on the CpG location.19 20 not associated with maternal RA disease activity or The most pronounced changes in DNA methylation medication use during pregnancy. http://ard.bmj.com/ occur during early pregnancy.7 11 Conclusions DNA methylation at 147 CpGs differed During embryogenesis, there are three germ between children born to mothers with RA and children layers that form in the developing fetus (ectoderm, born to mothers from the general population. It remains mesoderm and endoderm). When DNA methyla- unknown whether the identified associations are causal, tion is altered in early pregnancy, all germ layers and if so whether they are caused by the disease or are affected.21 22 treatment. More research, including replication of these Rheumatoid arthritis (RA) may be considered as results, is necessary in order to strengthen the relevance on September 30, 2021 by guest. Protected copyright. an adverse exposure during pregnancy.23 Therefore, of our findings for the later-life health of children born to it is plausible that maternal RA may induce changes mothers with RA. in fetal DNA methylation, and that it is related with the later-life health of the offspring. Inter- leukin-6 is known to influence DNA methylation.18 Adverse exposures in early life are associated with RA treatment during pregnancy includes among later-life health, which is referred to as the devel- others sulfasalazine (SSZ) and corticosteroids opmental origins of health and disease hypoth- such as prednisone. SSZ is a known folate antag- esis.1–5 Epigenetic processes are thought to be onist that crosses the placenta and could influence one of the mechanisms underlying the associa- DNA methylation in this respect.17 24 Furthermore, tions of early-life exposures and later-life health corticosteroids might influence DNA methyla- outcomes.6 7 DNA methylation is the best studied tion.16 Especially during early pregnancy, when the 8 9 © Author(s) (or their and understood epigenetic modification. Factors placenta is not completely developed, prednisone 25–28 employer(s)) 2019. Re-use that have been demonstrated to be associated with passively diffuses to the fetus. permitted under CC BY. fetal DNA methylation include maternal disease,7 In the current study we investigated whether Published by BMJ. malnutrition,10–13 smoking,14 placental insuffi- the DNA methylation profile of children born to 15 16 17 To cite: Ince-Askan H, ciency, corticosteroids, folate depletion and mothers with RA was different from that of chil- 18 Mandaviya PR, Felix JF, cytokines. DNA methylation usually occurs at dren born to mothers from the general popula- et al. Ann Rheum Dis cytosine-phosphate-guanine (CpG) sites.8 9 The tion. Furthermore, we investigated whether any 2019;78:1198–1204. effect of hypermethylation and hypomethylation on differentially methylated CpGs were associated 1198 Ince-Askan H, et al. Ann Rheum Dis 2019;78:1198–1204. doi:10.1136/annrheumdis-2018-214930 Rheumatoid arthritis Ann Rheum Dis: first published as 10.1136/annrheumdis-2018-214930 on 29 May 2019. Downloaded from with RA disease activity or medication use during pregnancy, or protocol. The Illumina array measures methylation status of 485 with indicators of future metabolic and cardiovascular diseases. 512 CpG sites in the gene and non-gene regions across the entire In addition, we examined whether these CpGs were associated human genome. To prevent possible batch effects, blood and with the expression of genes using expression quantitative trait cheek swab samples were measured in the same run. methylation (eQTM) analysis. Quality control and normalisation METHODS The data were preprocessed using the minfi package in R V.3.4.1 Study population ( www. r- project. org). Samples with incomplete or poor bisul- FEPRA study fite conversion, extension, hybridisation or specificity were This study is embedded in the Pregnancy-induced Amelioration excluded.34 In addition, samples with sex mismatch and samples of Rheumatoid Arthritis (PARA) study, a prospective cohort with a call rate <95% were removed. This quality control (QC) 29 study on pregnancy and RA. From 2002 to 2008, 369 female was done separately for blood samples and for cheek swab patients with RA who had a wish to conceive (or already preg- samples. During QC, 5 blood and 14 cheek swab samples from 30 31 nant) were enrolled. After participation in the PARA study, the FEPRA study were excluded, resulting in 80 and 57 samples, 196 children and their parents were invited to participate respectively. From the Generation R blood samples, 27 were in a follow-up study, the FEtal Programming in Rheumatoid excluded due to corticosteroid use or RA disease in the mother, Arthritis (FEPRA) study. For this study, 108 children with a and 32 were excluded during QC, resulting in 441 blood samples. mean age of 6.8 years (SD=1.3) visited Erasmus Medical Centre In addition, 87 cases with missing data from the Generation R in Rotterdam, and the parents of 85 children (all of European Study were excluded, leaving 354 samples to analyse. The inten- ancestry) gave informed consent for studies on DNA methyla- sity values were then quantile normalised using the incorporating tion of their children. Furthermore, the parents of 71 children Control Probe Adjustment and reduction of global CORrelation provided cheek swabs from their children. There were no statis- (CPACOR) workflow.34 Methylation at each CpG was calculated tical differences in baseline characteristics between the partici- as the beta value (beta=intensity of the methylated allele (M)/ pating and non-participating group. (intensity of the unmethylated allele (U)+M+100)), containing values from 0 to 1. Blood cell composition of the samples was Generation R Study estimated using the Houseman method with the Reinius refer- The control group consisted of children with a mean age of 6.0 ence set.35 36 The Reinius reference set is not yet validated in years (SD=0.4), included in the Generation R Study, a popula- children. However, it is the best method available, and it has tion-based prospective cohort study from pregnancy onwards in been used in other epigenetic studies in children.37 38 Probes with Rotterdam, the Netherlands.32 In this study, all pregnant women single nucleotide polymorphisms (SNPs) at single base exten- living in Rotterdam with a delivery date between April 2002 and sion, probes with improper binding, and CpGs on the X and January 2006 were invited to participate, and 9778 mothers Y chromosome were removed from the analysis.37–40 From the were enrolled.32 At the age of 6 years, DNA methylation was initial 485 512 CpGs, 32 057 were excluded during QC, leaving measured in a subgroup of 493 children of European ancestry. 453 456 CpGs for analysis. Data collection Statistical analysis FEPRA study For all subjects, descriptive statistics were calculated using Stata http://ard.bmj.com/ In the PARA study, data on mother (eg, disease activity (with V.14.1 (https://www.stata. com/ stata14/). Student’s t-tests and χ2 the Disease Activity Score in 28 joints using C reactive protein 3 31 tests were used to compare the baseline characteristics. For these levels, DAS28-CRP )) and child were collected.
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