Cord blood DNA methylation reflects cord blood C-reactive protein levels but not maternal levels: a longitudinal study and meta-analysis

Edwina H Yeung, Weihua Guan, Xuehuo Zeng, Lucas A Salas, Sunni L Mumford, Paula de Prado Bert, Evelien R van Meel, Anni Malmberg, Jordi Sunyer, Liesbeth Duijts, Janine F Felix, Darina Czamara, Esa Hämäläinen, Elisabeth B Binder, Katri Räikkönen, Jari Lahti, Stephanie J London, Robert M Silver, Enrique F Schisterman, Edwina H Yeung, Weihua Guan, Xuehuo Zeng, Lucas A Salas, Sunni L Mumford, Paula de Prado Bert, Evelien R van Meel, Anni Malmberg, Jordi Sunyer, Liesbeth Duijts, Janine F Felix, Darina Czamara, Esa Hämäläinen, Elisabeth B Binder, Katri Räikkönen, Jari Lahti, Stephanie J London, Robert M Silver, Enrique F Schisterman

Abstract

Background: Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes. C-reactive protein (CRP) is an inflammatory cytokine easily measured in blood. It has clinical value due to its reliability as a biomarker for systemic inflammation and can indicate cellular injury and disease severity. Elevated levels of CRP in adulthood are associated with alterations in DNA methylation. However, no studies have prospectively investigated the relationship between maternal CRP levels and newborn DNA methylation measured by microarray in cord blood with reasonable epigenome-wide coverage. Importantly, the timing of inflammation exposure during pregnancy may also result in different effects. Thus, our objective was to evaluate this prospective association of CRP levels measured during multiple periods of pregnancy and in cord blood at delivery which was available in one cohort (i.e., Effects of Aspirin in Gestation and Reproduction trial), and also to conduct a meta-analysis with available data at one point in pregnancy from three other cohorts from the Pregnancy And Childhood Epigenetics consortium (PACE). Secondarily, the impact of maternal randomization to low dose aspirin prior to pregnancy on methylation was assessed.

Results: Maternal CRP levels were not associated with newborn DNA methylation regardless of gestational age of measurement (i.e., CRP at approximately 8, 20, and 36 weeks among 358 newborns in EAGeR). There also was no association in the meta-analyses (all p > 0.5) with a larger sample size (n = 1603) from all participating PACE cohorts with available CRP data from first trimester (< 18 weeks gestation). Randomization to aspirin was not associated with DNA methylation. On the other hand, newborn CRP levels were significantly associated with DNA methylation in the EAGeR trial, with 33 CpGs identified (FDR corrected p < 0.05) when both CRP and methylation were measured at the same time point in cord blood. The top 7 CpGs most strongly associated with CRP resided in inflammation and vascular-related genes.

Conclusions: Maternal CRP levels measured during each trimester were not associated with cord blood DNA methylation. Rather, DNA methylation was associated with CRP levels measured in cord blood, particularly in gene regions predominately associated with angiogenic and inflammatory pathways.

Trial registration: Clinicaltrials.gov, NCT00467363, Registered April 30, 2007, http://www.clinicaltrials.gov/ct2/show/NCT00467363.

Keywords: C-reactive protein; DNA methylation; Developmental programming; Inflammation; Newborn; Pregnancy.

Conflict of interest statement

The authors report no competing interests.

References

    1. Bertran N, Camps J, Fernandez-Ballart J, Murphy MM, Arija V, Ferre N, et al. Evaluation of a high-sensitivity turbidimetric immunoassay for serum C-reactive protein: application to the study of longitudinal changes throughout normal pregnancy. Clinical chemistry and laboratory medicine : CCLM / FESCC. 2005;43(3):308–313.
    1. Azizia MM, Irvine LM, Coker M, Sanusi FA. The role of C-reactive protein in modern obstetric and gynecological practice. Acta Obstet Gynecol Scand. 2006;85(4):394–401.
    1. Sureshchandra S, Marshall NE, Wilson RM, Barr T, Rais M, Purnell JQ, et al. Inflammatory determinants of pregravid obesity in placenta and peripheral blood. Front Physiol. 2018;9:1089.
    1. Sureshchandra S, Wilson RM, Rais M, Marshall NE, Purnell JQ, Thornburg KL, et al. Maternal pregravid obesity remodels the DNA methylation landscape of cord blood monocytes disrupting their inflammatory program. J Immunol. 2017;199(8):2729–2744.
    1. Hantsoo L, Kornfield S, Anguera MC, Epperson CN. Inflammation: a proposed intermediary between maternal stress and offspring neuropsychiatric risk. Biol Psychiatry. 2018.
    1. Li Q, Wang YY, Guo Y, Zhou H, Wang X, Wang Q, et al. Effect of airborne particulate matter of 2.5mum or less on preterm birth: a national birth cohort study in China. Environ Int. 2018.
    1. Pitiphat W, Gillman MW, Joshipura KJ, Williams PL, Douglass CW, Rich-Edwards JW. Plasma C-reactive protein in early pregnancy and preterm delivery. Am J Epidemiol. 2005;162(11):1108–1113.
    1. Boggess KA, Lieff S, Murtha AP, Moss K, Jared H, Beck J, et al. Maternal serum C-reactive protein concentration early in pregnancy and subsequent pregnancy loss. Am J Perinatol. 2005;22(6):299–304.
    1. Tjoa ML, van Vugt JM, Go AT, Blankenstein MA, Oudejans CB, van Wijk IJ. Elevated C-reactive protein levels during first trimester of pregnancy are indicative of preeclampsia and intrauterine growth restriction. J Reprod Immunol. 2003;59(1):29–37.
    1. Wolf M, Kettyle E, Sandler L, Ecker JL, Roberts J, Thadhani R. Obesity and preeclampsia: the potential role of inflammation. Obstet Gynecol. 2001;98(5 Pt 1):757–762.
    1. Lapin B, Ownby D, Turyk M, Piorkowski J, Freels S, Chavez N, et al. Relationship between in utero C-reactive protein levels and asthma in at-risk children. Ann Allergy Asthma Immunol. 2015;115(4):282–287.
    1. Sonnenschein-van der Voort AM, Jaddoe VW, Moll HA, Hofman A, van der Valk RJ, de Jongste JC, et al. Influence of maternal and cord blood C-reactive protein on childhood respiratory symptoms and eczema. Pediatr Allergy Immunol. 2013;24(5):469–475.
    1. Fink NR, Chawes B, Bonnelykke K, Thorsen J, Stokholm J, Rasmussen MA, et al. Levels of systemic low-grade inflammation in pregnant mothers and their offspring are correlated. Sci Rep. 2019;9(1):3043.
    1. Morales E, Guerra S, Garcia-Esteban R, Guxens M, Alvarez-Pedrerol M, Bustamante M, et al. Maternal C-reactive protein levels in pregnancy are associated with wheezing and lower respiratory tract infections in the offspring. Am J Obstet Gynecol. 2011;204(2):164 e1–164 e9.
    1. Murphy VE, Smith R, Giles WB, Clifton VL. Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus. Endocr Rev. 2006;27(2):141–169.
    1. Ansar W. Biology of c reactive protein in health and disease. New York, NY: Springer Berlin Heidelberg; 2015. pages cm p.
    1. Ligthart S, Marzi C, Aslibekyan S, Mendelson MM, Conneely KN, Tanaka T, et al. DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. Genome Biol. 2016;17(1):255.
    1. Myte R, Sundkvist A, Van Guelpen B, Harlid S. Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort. Epigenetics. 2019;14(7):649–659.
    1. Sjaarda LA, Radin RG, Silver RM, Mitchell E, Mumford SL, Wilcox B, et al. Preconception low-dose aspirin restores diminished pregnancy and live birth rates in women with low-grade inflammation: a secondary analysis of a randomized trial. J Clin Endocrinol Metab. 2017;102(5):1495–1504.
    1. Felix JF, Joubert BR, Baccarelli AA, Sharp GC, Almqvist C, Annesi-Maesano I, et al. Cohort profile: Pregnancy And Childhood Epigenetics (PACE) consortium. Int J Epidemiol. 2018;47(1):22–3u.
    1. Bakulski KM, Feinberg JI, Andrews SV, Yang J, Brown S, Stephanie LM, et al. DNA methylation of cord blood cell types: applications for mixed cell birth studies. Epigenetics. 2016;11(5):354–362.
    1. Gervin K, Salas LA, Bakulski KM, van Zelm MC, Koestler DC, Wiencke JK, et al. Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data. Clin Epigenetics. 2019;11(1):125.
    1. Illumina I. Field guide to methylation methods: Illumina, Inc.; 2016 [updated 2/12/2020. Available from: .
    1. Berglind D, Muller P, Willmer M, Sinha I, Tynelius P, Naslund E, et al. Differential methylation in inflammation and type 2 diabetes genes in siblings born before and after maternal bariatric surgery. Obesity (Silver Spring) 2016;24(1):250–261.
    1. Su KY, Li MC, Lee NW, Ho BC, Cheng CL, Chuang YC, et al. Perinatal polychlorinated biphenyls and polychlorinated dibenzofurans exposure are associated with DNA methylation changes lasting to early adulthood: findings from Yucheng second generation. Environ Res. 2019;170:481–486.
    1. Nielsen FR, Bek KM, Rasmussen PE, Qvist I, Tobiassen M. C-reactive protein during normal pregnancy. Eur J Obstet Gynecol Reprod Biol. 1990;35(1):23–27.
    1. Kuzawa CW, Fried RL, Borja JB, McDade TW. Maternal pregnancy C-reactive protein predicts offspring birth size and body composition in metropolitan Cebu, Philippines. J Dev Orig Health Dis. 2017;8(6):674–681.
    1. Lowe R, Gemma C, Beyan H, Hawa MI, Bazeos A, Leslie RD, et al. Buccals are likely to be a more informative surrogate tissue than blood for epigenome-wide association studies. Epigenetics. 2013;8:4.
    1. Soegaard SH, Rostgaard K, Skogstrand K, Wiemels JL, Schmiegelow K, Hjalgrim H. Neonatal inflammatory markers are associated with childhood B-cell precursor acute lymphoblastic leukemia. Cancer Res. 2018;78(18):5458–5463.
    1. Kalva-Borato DC, Ribas JT, Parabocz GC, Borba LM, Maciel MAS, Santos FAD, et al. Biomarkers in non-complicated pregnancy: insights about serum myeloperoxidase and ultrasensitive C-reactive protein. Exp Clin Endocrinol Diabetes. 2019;127(9):585–589.
    1. Stokkeland LMT, Giskeodegard GF, Stridsklev S, Ryan L, Steinkjer B, Tangeras LH, et al. Serum cytokine patterns in first half of pregnancy. Cytokine. 2019;119:188–196.
    1. Logan CA, Thiel L, Bornemann R, Koenig W, Reister F, Brenner H, et al. Delivery mode, duration of labor, and cord blood adiponectin, leptin, and C-reactive protein: results of the population-based Ulm Birth Cohort studies. PLoS One. 2016;11(2):e0149918.
    1. Malek A, Bersinger NA, Di Santo S, Mueller MD, Sager R, Schneider H, et al. C-reactive protein production in term human placental tissue. Placenta. 2006;27(6-7):619–25.
    1. Sherrill HE, Jean P, Driver EC, Sanders TR, Fitzgerald TS, Moser T, et al. Pou4f1 Defines a subgroup of type I spiral ganglion neurons and is necessary for normal inner hair cell presynaptic Ca(2+) signaling. J Neurosci. 2019;39(27):5284–5298.
    1. Faryna M, Konermann C, Aulmann S, Bermejo JL, Brugger M, Diederichs S, et al. Genome-wide methylation screen in low-grade breast cancer identifies novel epigenetically altered genes as potential biomarkers for tumor diagnosis. FASEB J. 2012;26(12):4937–4950.
    1. Gonzalez-Jaramillo V, Portilla-Fernandez E, Glisic M, Voortman T, Ghanbari M, Bramer W, et al. Epigenetics and inflammatory markers: a systematic review of the current evidence. Int J Inflamm. 2019;2019:6273680.
    1. Hanion-Lundberg KM, Kirby RS, Gandhi S, Broekhuizen FF. Nucleated red blood cells in cord blood of singleton term neonates. Am J Obstet Gynecol. 1997;176(6):1149–1154.
    1. Olin A, Henckel E, Chen Y, Lakshmikanth T, Pou C, Mikes J, et al. Stereotypic immune system development in newborn children. Cell. 2018;174(5):1277–1292.
    1. Pereza N, Ostojic S, Kapovic M, Peterlin B. Systematic review and meta-analysis of genetic association studies in idiopathic recurrent spontaneous abortion. Fertil Steril. 2017;107(1):150–159.
    1. Ahmed SK, Mahmood N, Malalla ZH, Alsobyani FM, Al-Kiyumi IS, Almawi WY. C-reactive protein gene variants associated with recurrent pregnancy loss independent of CRP serum levels: a case-control study. Gene. 2015;569(1):136–140.
    1. Dwi Putra SE, Reichetzeder C, Hasan AA, Slowinski T, Chu C, Kramer BK, et al. Being born large for gestational age is associated with increased global placental DNA methylation. Sci Rep. 2020;10(1):927.
    1. Schisterman EF, Silver RM, Lesher LL, Faraggi D, Wactawski-Wende J, Townsend JM, et al. Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial. Lancet. 2014;384(9937):29–36.
    1. Yeung EH, Guan W, Mumford SL, Silver RM, Zhang C, Tsai MY, et al. Measured maternal prepregnancy anthropometry and newborn DNA methylation. Epigenomics. 2019;11(2):187–198.
    1. Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, et al. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014;30(10):1363–1369.
    1. Takai D, Jones PA. Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A. 2002;99(6):3740–3745.
    1. Touleimat N, Tost J. Complete pipeline for Infinium((R)) Human Methylation 450K BeadChip data processing using subset quantile normalization for accurate DNA methylation estimation. Epigenomics. 2012;4(3):325–341.
    1. Ghassabian A, Albert PS, Hornig M, Yeung E, Cherkerzian S, Goldstein RB, et al. Gestational cytokine concentrations and neurocognitive development at 7 years. Transl Psychiatry. 2018;8(1):64.
    1. Guxens M, Ballester F, Espada M, Fernandez MF, Grimalt JO, Ibarluzea J, et al. Cohort profile: the INMA--INfancia y Medio Ambiente--(Environment and Childhood) project. Int J Epidemiol. 2012;41(4):930–940.
    1. Kooijman MN, Kruithof CJ, van Duijn CM, Duijts L, Franco OH, van IJzendoorn MH, et al. The Generation R Study: design and cohort update 2017. Eur J Epidemiol. 2016;31(12):1243–1264.
    1. Girchenko P, Lahti M, Tuovinen S, Savolainen K, Lahti J, Binder EB, et al. Cohort profile: prediction and prevention of preeclampsia and intrauterine growth restriction (PREDO) study. Int J Epidemiol. 2017;46(5):1380–131g.
    1. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26(17):2190–2191.
    1. Breeze CE, Reynolds AP, van Dongen J, Dunham I, Lazar J, Neph S, et al. eFORGE v2.0: updated analysis of cell type-specific signal in epigenomic data. Bioinformatics. 2019;35(22):4767–4769.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit