Considerations in the Design, Conduct, and Interpretation of Studies in Epigenetic Epidemiology

  • Karin B. MichelsEmail author


Studies in epigenetic epidemiology may identify epigenetic aberrations associated with disease, link environmental and lifestyle factors to the epigenetic profile, or unveil epigenetic mechanisms underlying statistical associations between risk factors and disease outcomes. Epidemiologic studies provide the framework for identifying epigenetic biomarkers for disease risk or early detection of disease. Appropriate design considerations for studies in epigenetic epidemiology are imperative for their success. The tissue specificity of epigenetic marks represents a challenge in epigenetic epidemiology, and identification of disease markers in easily accessible surrogate tissues are essential for large-scale population-based studies. Nested case-control studies using biospecimens collected prior to onset of disease provide appropriate data to identify epigenetic changes preceding disease. Selecting a representative study population with sufficiently large sample size and appropriate comparison group is crucial for the validity and reproducibility of the results. Challenges in epigenetic epidemiology studies include confounding and effect modification, and identifying epigenetic marks with sufficient systematic interindividual variation.


Histone Modification Epigenetic Mark Neural Tube Defect Epigenetic Profile Individual CpGs 
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  1. 1.
    Gordis L (2009) Epidemiology, 4th edn. Saunders, Elsevier, PhiladelphiaGoogle Scholar
  2. 2.
    Doll R, Hill AB (1950) Smoking and carcinoma of the lung; preliminary report. Br Med J 2:739–748PubMedCrossRefGoogle Scholar
  3. 3.
    Michels KB (2010) The promises and challenges of epigenetic epidemiology. Exp Gerontol 45:297–301PubMedCrossRefGoogle Scholar
  4. 4.
    Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM (1995) Folate levels and neural tube defects. Implications for prevention. JAMA 274:1698–1702PubMedCrossRefGoogle Scholar
  5. 5.
    Wang L, Wang F, Guan J, Le J, Wu L, Zou J et al (2010) Relation between hypomethylation of long interspersed nucleotide elements and risk of neural tube defects. Am J Clin Nutr 91:1359–1367PubMedCrossRefGoogle Scholar
  6. 6.
    Chang H, Zhang T, Zhang Z, Bao R, Fu C, Wang Z et al (2011) Tissue-specific distribution of aberrant DNA methylation associated with maternal low-folate status in human neural tube defects. J Nutr Biochem. Feb 16 [epub]Google Scholar
  7. 7.
    Ohlsson R, Nystrom A, Pfeifer-Ohlsson S, Tohonen V, Hedborg F, Schofield P et al (1993) IGF2 is parentally imprinted during human embryogenesis and in the Beckwith-Wiedemann syndrome. Nat Genet 4:94–97PubMedCrossRefGoogle Scholar
  8. 8.
    Ogawa O, Eccles MR, Szeto J, McNoe LA, Yun K, Maw MA et al (1993) Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms’ tumour. Nature 362:749–751PubMedCrossRefGoogle Scholar
  9. 9.
    Lofton-Day C, Model F, Devos T, Tetzner R, Distler J, Schuster M et al (2008) DNA methy­lation biomarkers for blood-based colorectal cancer screening. Clin Chem 54:414–423PubMedCrossRefGoogle Scholar
  10. 10.
    Tanzer M, Balluff B, Distler J, Hale K, Leodolter A, Rocken C et al (2010) Performance of epigenetic markers SEPT9 and ALX4 in plasma for detection of colorectal precancerous lesions. PLoS One 5:e9061PubMedCrossRefGoogle Scholar
  11. 11.
    Chung W, Bondaruk J, Jelinek J, Lotan Y, Liang S, Czerniak B et al (2011) Detection of Bladder Cancer Using Novel DNA Methylation Biomarkers in Urine Sediments. Cancer Epidemiol Biomarkers Prev 20:1483–1491PubMedCrossRefGoogle Scholar
  12. 12.
    Kagan J, Srivastava S, Barker PE, Belinsky SA, Cairns P (2007) Towards Clinical Application of Methylated DNA Sequences as Cancer Biomarkers: A Joint NCI’s EDRN and NIST Workshop on Standards, Methods, Assays, Reagents and Tools. Cancer Res 67:4545–4549PubMedCrossRefGoogle Scholar
  13. 13.
    Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R et al (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20:2429–2440PubMedCrossRefGoogle Scholar
  14. 14.
    Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH et al (2009) Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 27:5410–5417PubMedCrossRefGoogle Scholar
  15. 15.
    Jacinto FV, Esteller M (2007) MGMT hypermethylation: a prognostic foe, a predictive friend. DNA Repair (Amst) 6:1155–1160CrossRefGoogle Scholar
  16. 16.
    Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS (1996) Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 274:2057–2059PubMedCrossRefGoogle Scholar
  17. 17.
    Ellsworth DL, Ellsworth RE, Love B, Deyarmin B, Lubert SM, Mittal V et al (2004) Genomic patterns of allelic imbalance in disease free tissue adjacent to primary breast carcinomas. Breast Cancer Res Treat 88:131–139PubMedCrossRefGoogle Scholar
  18. 18.
    Kurose K, Hoshaw-Woodard S, Adeyinka A, Lemeshow S, Watson PH, Eng C (2001) Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour-microenvironment interactions. Hum Mol Genet 10:1907–1913PubMedCrossRefGoogle Scholar
  19. 19.
    Cui H, Cruz-Correa M, Giardiello FM, Hutcheon DF, Kafonek DR, Brandenburg S et al (2003) Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 299:1753–1755PubMedCrossRefGoogle Scholar
  20. 20.
    Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez NS, Vilaythong J et al (2005) MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst 97:1330–1338PubMedCrossRefGoogle Scholar
  21. 21.
    Yan PS, Venkataramu C, Ibrahim A, Liu JC, Shen RZ, Diaz NM et al (2006) Mapping geographic zones of cancer risk with epigenetic biomarkers in normal breast tissue. Clin Cancer Res 12:6626–6636PubMedCrossRefGoogle Scholar
  22. 22.
    Riazalhosseini Y, Hoheisel JD (2008) Do we use the appropriate controls for the identification of informative methylation markers for early cancer detection? Genome Biol 9:405PubMedCrossRefGoogle Scholar
  23. 23.
    Ahuja N, Li Q, Mohan AL, Baylin SB, Issa JP (1998) Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res 58:5489–5494PubMedGoogle Scholar
  24. 24.
    Gronniger E, Weber B, Heil O, Peters N, Stab F, Wenck H et al (2010) Aging and chronic sun exposure cause distinct epigenetic changes in human skin. PLoS Genet 6:e1000971PubMedCrossRefGoogle Scholar
  25. 25.
    Marsit CJ, Koestler DC, Christensen BC, Karagas MR, Houseman EA, Kelsey KT (2011) DNA methylation array analysis identifies profiles of blood-derived DNA methylation associated with bladder cancer. J Clin Oncol 29:1133–1139PubMedCrossRefGoogle Scholar
  26. 26.
    Kim M, Long TI, Arakawa K, Wang R, Yu MC, Laird PW (2010) DNA methylation as a ­biomarker for cardiovascular disease risk. PLoS One 5:e9692PubMedCrossRefGoogle Scholar
  27. 27.
    Nadeau K, McDonald-Hyman C, Noth EM, Pratt B, Hammond SK, Balmes J et al (2010) Ambient air pollution impairs regulatory T-cell function in asthma. J Allergy Clin Immunol 126:845–852, e810PubMedCrossRefGoogle Scholar
  28. 28.
    Uddin M, Koenen KC, Aiello AE, Wildman DE, De los Santos R, Galea S (2011) Epigenetic and inflammatory marker profiles associated with depression in a community-based epidemiologic sample. Psychol Med 41:997–1007PubMedCrossRefGoogle Scholar
  29. 29.
    Friedrich MG, Weisenberger DJ, Cheng JC, Chandrasoma S, Siegmund KD, Gonzalgo ML et al (2004) Detection of methylated apoptosis-associated genes in urine sediments of bladder cancer patients. Clin Cancer Res 10:7457–7465PubMedCrossRefGoogle Scholar
  30. 30.
    Waterland RA, Michels KB (2007) Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr 27:363–388PubMedCrossRefGoogle Scholar
  31. 31.
    Talens RP, Boomsma DI, Tobi EW, Kremer D, Jukema JW, Willemsen G et al (2010) Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J 24:3135–3144PubMedCrossRefGoogle Scholar
  32. 32.
    Ma DK, Jang MH, Guo JU, Kitabatake Y, Chang ML, Pow-Anpongkul N et al (2009) Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323:1074–1077PubMedCrossRefGoogle Scholar
  33. 33.
    Bernstein BE, Meissner A, Lander ES (2007) The mammalian epigenome. Cell 128:669–681PubMedCrossRefGoogle Scholar
  34. 34.
    Laird PW (2010) Principles and challenges of genomewide DNA methylation analysis. Nat Rev Genet 11:191–203PubMedCrossRefGoogle Scholar
  35. 35.
    Issa JP (2003) Age-related epigenetic changes and the immune system. Clin Immunol 109:103–108PubMedCrossRefGoogle Scholar
  36. 36.
    Zhang FF, Cardarelli R, Carroll J, Fulda KG, Kaur M, Gonzalez K et al (2011) Significant ­differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood. Epigenetics 6:623–629Google Scholar
  37. 37.
    Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J et al (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462:315–322PubMedCrossRefGoogle Scholar
  38. 38.
    Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL et al (2009) Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 5:e1000602PubMedCrossRefGoogle Scholar
  39. 39.
    Langevin SM, Houseman EA, Christensen BC, Wiencke JK, Nelson HH, Karagas MR et al (2011) The influence of aging, environmental exposures and local sequence features on the variation of DNA methylation in blood. Epigenetics 6:630–637CrossRefGoogle Scholar
  40. 40.
    Marsit CJ, Christensen BC, Houseman EA, Karagas MR, Wrensch MR, Yeh RF et al (2009) Epigenetic profiling reveals etiologically distinct patterns of DNA methylation in head and neck squamous cell carcinoma. Carcinogenesis 30:416–422PubMedCrossRefGoogle Scholar
  41. 41.
    Gort EH, Suijkerbuijk KP, Roothaan SM, Raman V, Vooijs M, van der Wall E et al (2008) Methylation of the TWIST1 promoter, TWIST1 mRNA levels, and immunohistochemical expression of TWIST1 in breast cancer. Cancer Epidemiol Biomarkers Prev 17:3325–3330PubMedCrossRefGoogle Scholar
  42. 42.
    Diplas AI, Lambertini L, Lee MJ, Sperling R, Lee YL, Wetmur J et al (2009) Differential expression of imprinted genes in normal and IUGR human placentas. Epigenetics 4:235–240PubMedGoogle Scholar
  43. 43.
    Fourkala EO, Hauser-Kronberger C, Apostolidou S, Burnell M, Jones A, Grall J et al (2010) DNA methylation of polycomb group target genes in cores taken from breast cancer centre and periphery. Breast Cancer Res Treat 120:345–355PubMedCrossRefGoogle Scholar
  44. 44.
    Bock C, Walter J, Paulsen M, Lengauer T (2008) Inter-individual variation of DNA methy­lation and its implications for large-scale epigenome mapping. Nucleic Acids Res 36:e55PubMedCrossRefGoogle Scholar
  45. 45.
    Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428PubMedCrossRefGoogle Scholar
  46. 46.
    Zhang FF, Morabia A, Carroll J, Gonzalez K, Fulda K, Kaur M et al (2011) Dietary patterns are associated with levels of global genomic DNA methylation in a cancer-free population. J Nutr 141:1165–1171PubMedCrossRefGoogle Scholar
  47. 47.
    Zhu ZZ, Sparrow D, Hou L, Tarantini L, Bollati V, Litonjua AA et al (2011) Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence, and mortality in elderly individuals: the Normative Aging Study. Cancer Causes Control 22:437–447PubMedCrossRefGoogle Scholar
  48. 48.
    Yoshida T, Yamashita S, Takamura-Enya T, Niwa T, Ando T, Enomoto S et al (2011) Alu and Satalpha hypomethylation in Helicobacter pylori-infected gastric mucosae. Int J Cancer 128:33–39PubMedCrossRefGoogle Scholar
  49. 49.
    Saito K, Kawakami K, Matsumoto I, Oda M, Watanabe G, Minamoto T (2010) Long interspersed nuclear element 1 hypomethylation is a marker of poor prognosis in stage IA non-small cell lung cancer. Clin Cancer Res 16:2418–2426PubMedCrossRefGoogle Scholar
  50. 50.
    Bock C, Paulsen M, Tierling S, Mikeska T, Lengauer T, Walter J (2006) CpG island methy­lation in human lymphocytes is highly correlated with DNA sequence, repeats, and predicted DNA structure. PLoS Genet 2:e26PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  1. 1.Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology and Reproductive BiologyBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  2. 2.Department of EpidemiologyHarvard School of Public HealthBostonUSA

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