Altered dna-methylation in children born to mothers with rheumatoid arthritis during pregnancy

Background: Exposures during early life are associated with later-life health, which is referred to as the Developmental Origins of Health and Disease hypothesis[. Epigenetic processes are thought to be one of the mechanisms underlying this hypothesis. DNA-methylation is the best studied and understood epigenetic modification. DNA-methylation of the fetus in utero may be influenced by multiple factors, including maternal disease[. Objectives: To determine whether the DNA-methylation profile of children born to women with RA is different from children born to women from the general population. Furthermore to determine which pathways are associated with the significantly differentially methylated CpG sites. Methods: For the current study, blood from 80 children with a mean age of 6.82(SD=1.28) born to women with RA, who were followed prospectively during pregnancy and postpartum in the PARA-study[, was used to measure genomewide DNA-methylation using the Infinium Illumina Human-Methylation 450 k BeadChip. DNA from 345 children with a mean age of 6.04(SD=0.39) born to women from the population-based Generation R study[ were used as controls, also followed prospectively during pregnancy and postpartum. Linear mixed models were used to analyse differences in methylation between these groups. The models were corrected for age, BMI(SDS) and sex of the child, gestational age at delivery, maternal age, folic acid use during pregnancy, socioeconomic status, maternal smoking during pregnancy, white blood cell subtypes and technical batch. Results: In total 770 CpGs were significantly different between the 2 groups at Bonferroni threshold p=1.08*10–7(see table 1. for top 10 sites). In addition, pathway analysis resulted in 4 statistically significant enriched pathways. The top 2 pathways were the FOXO signalling pathway consisting of 16 genes(p=3.39*10–4) and mTOR signalling pathway consisting of 17 genes(p=5.65*10–4). These pathways are known for regulating the glucose and lipid metabolism, respectively. Table 1 Top 10 methylation sites from the linear mixed model Conclusions: This study demonstrates that children born to women with RA have a different methylation profile compared with children born to mothers from the general population. References: Barouki R, Gluckman PD, Grandjean P, Hanson M, Heindel JJ. Developmental origins of non-communicable disease: implications for research and public health. Environ Health 2012;11:42. Hogg K, Price EM, Hanna CW, Robinson WP. Prenatal and perinatal environmental influences on the human fetal and placental epigenome. Clin Pharmacol Ther 2012;92:716–26. de Man YA, Dolhain RJ, van de Geijn FE, Willemsen SP, Hazes JM. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum 2008;59:1241–8. Kooijman MN, Kruithof CJ, van Duijn CM, Duijts L, Franco OH, van IMH, et al. The Generation R Study: design and cohort update 2017. Eur J Epidemiol 2016;31:1243–64. Acknowledgements: Funding: this study was funded by the Dutch Arthritis Association(Reumafonds), a non-commercial fund raising organisation. Disclosure of Interest: None declared DOI: 10.1136/annrheumdis-2018-eular.4493 Citation: Ann Rheum Dis, volume 77, supplement Suppl, year 2018, page A298Session: Rheumatoid arthritis – comorbidity and clinical aspects