Council for the Advancement of Nursing Science

DNA methylation in complex disease:Applications in nursing research, practice, and policyMichelle L. Wright, MS, RNa, Jody L. Ralph, PhD, RNa, Joyce E. Ohm, PhDb,

Cindy M. Anderson, PhD, WHNP-BC, FAANa,*aDepartment of Nursing, College of Nursing and Professional Disciplines, University of North Dakota, Grand Forks, ND

bDepartment of Biochemistry and Molecular Biology, School of Medicine and Health Sciences,

University of North Dakota, Grand Forks, ND

a r t i c l e i n f o

Article history:Received 5 February 2013Revised 23 April 2013Accepted 28 April 2013

Keywords:EpigeneticsDNA methylationGeneeenvironment interactionPolicy

* Corresponding author: Cindy M. Anderson,Dakota, 430 Oxford Street Stop 9025, Grand

E-mail address: cindyandersongfnd@gma

0029-6554/$ - see front matter � 2013 Elsevihttp://dx.doi.org/10.1016/j.outlook.2013.04.01

a b s t r a c t

DNA methylation is an epigenomic modification that is essential to normalhuman development and biological processes. DNA methylation patternsare heritable and dynamic throughout the life span. Environmental expo-sures can alter DNA methylation patterns, contributing to the developmentof complex disease. Identification and modulation of environmental factorsinfluencing disease susceptibility through alterations in DNA methylationare amenable to nursing intervention and form the basis for individualizedpatient care. Here we describe the evidence supporting the translation ofDNA methylation analyses as a tool for screening, diagnosis, and treatmentof complex disease in nursing research and practice. The ethical, legal,social, and economic considerations of advances in genomics are consideredas a model for epigenomic policy. We conclude that contemporary andinformed nurse scientists and clinicians are uniquely poised to applyinnovations in epigenomic research to clinical populations and developappropriate policies that guide equitable and ethical use of new strategiesto improve patient care.

Cite this article: Wright, M. L., Ralph, J. L., Ohm, J. E., & Anderson, C. M. (2013, AUGUST). DNA methylation

in complex disease: Applications in nursing research, practice, and policy. Nursing Outlook, 61(4), 235-

241. http://dx.doi.org/10.1016/j.outlook.2013.04.010.

Introduction

Advances in epigenomic research are leading to greaterunderstanding of the factors associated with complexdisease processes. DNA methylation is an epigeneticprocess that predominates during development andcan be modulated throughout postnatal life. Epi-genomics represents a logical target of investigationfor geneeenvironment interactions because of thedynamic and potentially reversible nature of endoge-nous and exogenous influences that modulate thegenome across the life span (Feinberg, 2008). Many

Department of Nursing, CForks, ND 58202-9025.il.com (C.M. Anderson).

er Inc. All rights reserved0

environmental exposures are modifiable risk factorsfor disease that are amenable to nursing interventions(Davis & Uthus, 2004; Kargul & Laurent, 2009; F. F.Zhang et al., 2011). Nurses, nurse scientists, andadvanced practice nurses play a vital role in complexdisease prevention, screening, and management. Asmembers of interdisciplinary teams, nurses can useadvances in epigenomic techniques to better evaluateand address levels of health and disease risk. There-fore, investigating how environment and epigenomicsinteract to mechanistically contribute to complexdisease produces knowledge for the development ofbetter treatment and prevention methods (Custovic,

ollege of Nursing and Professional Disciplines, University of North

.

Nur s Out l o o k 6 1 ( 2 0 1 3 ) 2 3 5e 2 4 1236

Marinho, & Simpson, 2012; NIEHS, National Institute ofEnvironmental Health Sciences, 2012).

Rapid advances in epigenomics present real andpotential ethical, legal, social, and economic chal-lenges, which must be addressed by epigenomicpolicy development for equitable application andaccess for the public. The body of literature in epi-genomics has grown exponentially, challenging theability of researchers, educators, practitioners, andpolicy makers to stay abreast of new developmentsthat form the basis for increased understanding ofthe mechanisms that lead to complex disease statesand their translation to improve health. Our articleaims to describe (a) the process of DNA methylationand its association with complex disease; (b) theevidence supporting the translation of DNA methyl-ation analyses as a tool for screening, diagnosis, andtreatment of complex disease; and (c) the ethical,legal, and socioeconomic policy implications of epi-genomic investigations in research and clinicalpractice.

DNA Methylation in Complex Disease

Epigenetic changes are chemical alterations to thegenome that do not change the DNA sequence butmay lead to a specific phenotype, disease state, orother observable characteristics (Berger, Kouzarides,Shiekhattar, & Shilatifard, 2009). The epigenome isthe composite of changes “above the genes” thatcollectively modulate gene expression. DNA methyl-ation is an epigenetic change that influences geneexpression through the addition of a methyl group toa cytosine nucleotide base linked to a guaninenucleotide base, commonly referred to as a CpGdinucleotide (Baccarelli, Rienstra, & Benjamin, 2010).Promoter regions of genes associated with the startof transcription often have dense regions of CpGdinucleotides. Gain of methylation in a CpG dinu-cleotide may attenuate gene expression, whereasmethylation loss has the opposite effect. Inappro-priate gene silencing because of the gain of meth-ylation or inappropriate gene expression because ofthe loss of methylation is becoming increasinglyimportant to the study of complex disease (Ellingeret al., 2010; Kargul & Laurent, 2009; Nelson, DeMarzo, & Yegnasubramanian, 2009).

The process of DNA methylation is central toestablishment and maintenance cellular differentia-tion, active during development and throughout thelife span. Aberrant DNA methylation may directlyparticipate in the pathogenesis of complex disease orserve as a risk factor that, when exposed to endog-enous or exogenous challenges, leads to the devel-opment of complex disease phenotypes (Chung &Auger, 2013). For example, the embryologic period isa vulnerable time during which there is a period ofrapid cell division and remodeling of the epigenome.

Genome-wide demethylation at conception (with theexception of imprinted genes) is followed by genome-wide remethylation at implantation (Seisenberger,Peat, & Reik, 2013). Somatic maintenance of epige-netic patterns results in mitotic transmission, cata-lyzed by the enzyme DNA methyltransferase (DNMT)1. Methylation patterns in the germ-line cells havethe potential to perpetuate to subsequent genera-tions, transmitting parental epigenomic marks tooffspring. Epigenetic patterns established in gametesand early embryos are transmitted from one cellgeneration to another, accounting for transgenera-tional inheritance. The influence of perinatal factorsthat have the potential to alter the offspring epi-genome is significant, reinforcing the need to opti-mize maternal health for long-term outcomes. In ananimal model, birth weight was identified as a deter-minant of aberrant DNA methylation, influencingneurologic function in offspring because of alteredcell cycle during development and gene expression inadulthood (Grissom & Reyes, 2012). The precisemanner by which factors alter the epigenome are notyet fully elucidated; however, both exogenous andendogenous factors are believed to play a role indefining the epigenome.

Exogenous factors with the potential to alter theepigenome include diet, exercise, toxin exposure,obesity, and behaviors associated with tobacco,alcohol, and drug use (Lim, 2012). DNA methylationis directly affected by dietary micronutrient intake.Folate, choline, betaine, and other B vitaminsparticipate in one-carbon metabolism and areresponsible for catalyzing the process of methyldonation (Anderson et al., 2012). Such dietary influ-ences shape the epigenome during development,dependent on maternal methyl donor intake, and aresources of dynamic alterations throughout the lifespan. For example, the phenotype of offspring wasaltered with supplementation of methyl donors inthe maternal diet during pregnancy in a mousemodel (Waterland et al., 2006). In addition to nutri-tion, long-term strenuous physical activity alters theepigenome, improving health (Sanchis-Gomar et al.,2012). Geneeenvironment interactions that influ-ence the epigenome have been implicated in humanathletic performance (Brutsaert & Parra, 2006),contributing to maximally effective pulmonary,cardiovascular, and muscular functions.

The presence of toxins that induce epigeneticmodification is unavoidable, as they are present indrinking water, food and beverage containers, house-hold dust, and various consumer products (Latham,Sapienza, & Engel, 2012). Examples include bisphenolA (BPA), a synthetic estrogen-mimetic agent in plasticbottles used for multiple purposes, including infantfeeding (Singh & Li, 2012) and obesogens, which areorganotin compounds that modulate adipogenesisthrough DNA hypomethylation (Kirchner, Kieu, Chow,Casey, & Blumberg, 2010). Tobacco is a known epige-netic modifier, inducing methylation of tumor

Nur s Ou t l o o k 6 1 ( 2 0 1 3 ) 2 3 5e 2 4 1 237

suppressor genes (Ostrow et al., 2013) associated withuroepithelial cell carcinoma (Brait et al., 2013). Loss ofsite-specific methylation resulting from smoking wasidentified in peripheral blood cells among individualswith less than one-halfepack year exposure (Philibert,Beach, & Brody, 2012). Prenatal tobacco exposure,coupled with unfavorable early-life conditions, triggersaberrant DNA methylation associated with loss ofimpulse control, including eating disorders, alco-holism, and indiscriminate social behaviors (Archer,Oscar-Berman, Blum, & Gold, 2012). Alcohol (EtOH)use has the potential to alter the epigenome, associ-ated with behavioral changes related to tolerance anddependence (Starkman, Sakharkar, & Pandey, 2012).The capacity for transgenerational inheritancepatterns of DNA methylation suggests that environ-mental exposures may have pathological conse-quences that extend beyond the risks associated withdirect exposure (Figure 1).

Endogenous factors shown to alter the epigenomeinclude the hormonal milieu, stress, pathogens, andgenetic factors. Endocrine disruptors, substances thatalter steroid hormone metabolism, can alter the func-tion of sensitive tissues, including nervous, thyroid,and reproductive, through alterations in the epi-genome (Waring & Harris, 2011). The epigenomicmarks triggered by endocrine disruptors have thepotential to be transmitted across generations, pre-senting significant health risks. In an animal study,maternal exposure to the endocrine disruptor BPAaltered offspring phenotype through DNA methylation(Anderson et al., 2012). The hypomethylation inducedby BPA was countered by maternal dietary supple-mentation of methyl donors (Bernal & Jirtle, 2010),providing further evidence of the responsiveness to theepigenome to environmental factors.

Figure 1 e Influence of DNA Methylation in ChronicDisease. Alteration in DNA Methylation byExogenous and Endogenous Factors Can Contributeto the Increased Susceptibility of Complex Diseasein Individuals and the Transmission of Risk AcrossGenerations.

Endogenous stressors during vulnerable periods caninduce an altered phenotype or predispose a pheno-type alteration when combined with a so-called“second hit” (Day & James, 1998). In an animal model,chronic and unpredictable maternal separationeinduced DNA methylation aberrations were associatedwith behavioral change in adult offspring (Franklinet al., 2010; Weiss, Franklin, Vizi, & Mansuy, 2011).When postnatal separation was combined withmaternal stress, behavioral deficits worsened,demonstrating the exposure of epigenetic predisposi-tion through additional risks. Furthermore, femalestransmitted behavioral deficits to a subsequentgeneration, evidence of the heritable long-term impli-cations of the disordered epigenome.

Changes in epigenetic patterning may also occur asthe result of exposure to different microbial commu-nities. In animal models, altered composition of resi-dent microbes early in life results in later immunedysfunction (Kendall, 1915; Olszak et al., 2012). Olszaket al. determined that altered microbial compositionearly in life led to aberrant methylation patterns in theCXCL16 gene in the lung and colon. Hypermethylationof the CXCL16 gene results in accumulation of Tlymphocytes involved in inflammatory processes,priming the host for hypersensitivity immuneresponses such as those seen in asthma and inflam-matory bowel disease. Single-gene mutations in genesinvolved in DNAmethylation processes, such as DNMTenzymes, are key targets for the evolution of complexdisease (Huidobro, Fernandez, & Fraga, 2013). Modifi-able endogenous factors represent targets for preven-tion, whereas those factors that are nonmodifiableprovide targets for manipulation of the epigenome,serving as the basis for novel treatment strategies.

Early investigation into DNA methylation in cancerbiology provided evidence of aberrant methylation,including both gain and loss (Cui, Horon, Ohlsson,Hamilton, & Feinberg, 1998; Jones & Baylin, 2002).Malignancies associated with aberrant hyper-methylation in promoter regions of tumor suppressorgenes are related to reduced expression. The resultinggene silencing is associated with carcinogenesis,leading to oncogenic conditions including renal (Luet al., 2013), breast (Mirza et al., 2013), nonesmall celllung (Zhao et al., 2013), and colon (Y. Zhang, Li, & Chen,2013) cancer. Genome-wide methylation loss has beenidentified in multiple forms of cancer (Kim et al., 2013),with recent gene-specific evidence of hypomethylationin bladder (Cheng, Deng, Wang, Zhang, & Su, 2012),prostate (Yang et al., 2013), and breast (Bi, Li, & Yang,2013) cancer. More recently, investigations intocomplex disease etiology in other conditions haveidentified epigenetic aberrations in DNA methylationassociated with such diverse conditions as osteoar-thritis (Fernandez-Tajes et al., 2013), cardiovascular(Kim et al., 2013), Alzheimer’s (Chouliaras et al., 2013),and Hirschsprung’s (Tang et al., 2013) disease. Mostrecently, our laboratory identified a panel of genes withboth gain and loss of methylation that represent

Nur s Out l o o k 6 1 ( 2 0 1 3 ) 2 3 5e 2 4 1238

a likely biomarker for early identification ofpreeclampsia, a pregnancy-specific complex syndromeassociated with heritable risk (Anderson et al., 2013).The investigation of the epigenome in combinationwith more traditional methods of genomic investiga-tion have the potential to reveal novel targets that willtranslate to new opportunities for screening, treat-ment, and management of complex disease.

DNA Methylation Translation in Clinical Care

The dynamic developments in epigenomic researchhave generated new targets for screening, diagnosis,and treatment of complex disease. The identification ofepigenetic markers to elucidate biological mechanismsof complex disease processes, such as cardiovasculardisease, schizophrenia, and lupus, has been increasingin recent years (Rodenhiser & Mann, 2006). Increasedmethylation of the FOXP3 gene decreases expression ofregulatory T lymphocytes, promoting inflammationassociated with acute coronary syndrome (Jia et al.,2013). In an animal model, maternal supplementationwith methyl donors protected against atherosclerosisthrough reduced T lymphocyte inflammatory cytokineexpression (Delaney et al., 2013). Epigenomic alterationin immune function is associated with systemic lupuserythematosus (SLE), with T lymphocyte DNA deme-thylation contributing to lupus flare severity (Sawalhaet al., 2012). SLE can also be induced by epigenetic-modifying drugs (e.g., procainamide and hydralazine),indicating a role for exogenous factors in diseasedevelopment (Patel & Richardson, 2013). In an animalmodel, DNA methylation that was altered because ofrestriction of dietary methylation donors and cofactorscontributed to a lupus-like phenotype (Strickland et al.,2013), underscoring the significant role of nutrition inthe shaping of the epigenome. The gender differencesfavoring females in the development of autoimmunediseasemay be associatedwith demethylation of geneson the inactivated X chromosome, providing mecha-nistic evidence of the predisposition to lupus amongfemales (Hewagama et al., 2013).

Global hypomethylation has been found in individ-uals with schizophrenia, most prominent in individ-uals with early-onset disease and reversed withhaloperidol treatment (Melas et al., 2012). In first-episode schizophrenia, site-specific differential DNAmethylation was identified as an early biomarker ofdisease (Nishioka et al., 2013). Furthermore, differentialDNA methylation of glutaminergic receptors inperipheral white blood cells was associated withincreased risk of schizophrenia (Kordi-Tamandani,Dahmardeh, & Torkamanzehi, 2013), whereas meth-ylation of the brain-derived neurotropic factor wasassociated with reduced schizophrenia risk (Kordi-Tamandani, Sahranavard, & Torkamanzehi, 2012).Fetal exposure to famine in Northern Han Chinesepregnant women was associated with site-specific

methylation linked to future development of schizo-phrenia, providing evidence of prenatal triggers fordifferential methylation underlying future risk ofdisease (Xu et al., 2012). Proposed pathways underlyingthe influence of prenatal nutrition on future develop-ment of schizophrenia likely involve the essentialmicronutrients folate and vitamin B12, central to one-carbon metabolism (Kirkbride et al., 2012).

Patterns of methylation associated with a specificphenotype, such as susceptibility to complex disease,have the potential for identification of individuals atrisk and serve as the basis for novel treatment. Treat-ments based on epigenetic markers have beenapproved and used successfully in complex diseases(Ho, Turcan, & Chan, 2013; Rodriguez-Paredes &Esteller, 2011). The DNMT inhibitors, 5-azacitidineand decitabine, were approved for treatment of mye-lodysplastic syndrome (Kaminskas, Farrell, Wang,Sridhara, & Pazdur, 2005; Wijermans, Lubbert,Verhoef, Klimek, & Bosly, 2005). These medicationsact during DNA replication to decrease the levels ofDNMT contributing to hypomethylation of genes,enhancing gene expression. Additional key areas ofepigenomic cancer research include the epigeneticagents aimed at sensitizing the chemoresistant tumorsto the traditional chemotherapeutic modalities (Ho,Turcan, & Chan, 2013). Interestingly, investigations ofseveral well-known medications have revealed induc-tion of epigenomic mechanisms, namely hypo-methylation and demethylation. These medicationsinclude the antiarrhythmic drug procainamide (Lee,Yegnasubramanian, Lin, & Nelson, 2005), the anti-diuretic hydralazine (Zambrano et al., 2005), and theantiepileptic and mood stabilizer valproic acid (Detich,Bovenzi, & Szyf, 2003).

The identification of genes and locations withingenes of known methylation in individual CpG dinu-cleotides provides an opportunity to determine themechanistic and potential functional consequences ofdifferential methylation and their contributions todisease phenotype. Application of geneeenvironmentinteraction models will be useful in designing studiesto determine environmental factors that modify DNAmethylation patterns. The clinical translation of epi-genomic biomarkers that detect disease risk andphenotype has the potential to launch new ways toidentify susceptibility in individuals and familymembers across the life span and to implement inter-ventions for effective primary, secondary, and tertiaryprevention.

Implications of Epigenomics in NursingPractice, Research, and Policy

Nursing Practice

Significant advances have been made in the identifi-cation of the epigenetic marks associated with

Nur s Ou t l o o k 6 1 ( 2 0 1 3 ) 2 3 5e 2 4 1 239

complex disease phenotypes. However, application ofclinical investigations of DNA methylation status islimited by the use of genomic principles across alllevels of nursing practice. As a profession, nurses arepoised to deliver cutting-edge evidence-based care andpatient education based on the application of epi-genomics in practice. For effective translation of epi-genomics into practice, educational curricula nowinclude essential nursing competencies applicable toall registered nurses (Calzone, Jenkins, Prows, &Masny, 2011). In addition to academic competencies(Consensus Panel, 2008), continuing education forpracticing nurses is essential in the preparation of thenursing workforce to incorporate genomics in clinicalpractice. Essential genetic and genomic competenciesfor advanced practice registered nurses, clinical nurseleaders, nurse educators, nurse administrators, andnurse scientists (Greco, Tinley, & Seibert, 2012) andhealth professionals in other disciplines (NationalCoalition for Health Professional Education in GeneticsSteering Committee, 2007) provide the opportunity toprepare practicing health care providers in thecontinued development of knowledge, skills, and atti-tudes necessary for genomic clinical practice(Consensus Panel, 2011). Epigenomics is a new andevolving field to which the competencies and profes-sional development in genetics and genomics can beapplied as the foundation for current, evidence-basedpractice.

Professional nurses are involved in obtainingfamily history and biological samples for use in theidentification of complex diseases with epigeneticetiology. Protection of patient privacy and the provi-sion of informed consent are of paramount impor-tance in this process. As with other types of genomicand genetic data, epigenomic information is difficultto de-identify compared with many other laboratorytests as it is uniquely linked to a single individual(Badzek, Henaghan, Turner, & Monsen, 2012). Theepigenomic profile is distinct from an individual’sgenotype as each person’s environmental exposuresgenerate a unique methylome. The value in incorpo-ration of both genomic and epigenomic data simul-taneously has the potential to identify synergisticeffects and the potential for personalized health care(Chadwell, 2013).

Research

Epigenomic research findings are advancing at a stag-gering pace, creating challenges for synthesis and useto improve patient outcomes. The rapid pace ofdiscovery and methodological and clinical applicationof epigenomic research represents a challenge to thegeneration and clinical application of findings. Nursescientists are increasingly involved in genetic researchas independent scientists or collaborative members ofinterdisciplinary research teams. As such, they arefaced with unique challenges of translating technicallaboratory findings to study participants and later

determining how to best translate those findings intoclinical practice.

For example, the genome-wide approach for theidentification of known and novel differentially meth-ylated genes may result in incidental findings (Ayuso,Millan, Mancheno, & Dal-Re, 2013). The premise ofmutual benefit to researchers and research partici-pants has created debate as to how or whether theinvestigator is obligated to report such findings to theparticipant (Kaye, 2012). The challenge of communi-cating incidental findings identified by secondary usersof large epigenomic databases is even more chal-lenging, as there is no direct relationship between theprimary investigator and the participant in such anal-yses. Incidental findings also represent a challenge inpractice as not all genes affected by differential DNAmethylation are associated with known function(Ayuso et al., 2013). In situations of hereditary riskidentified by a classic genetic mutation with a predict-able inheritance pattern, the potential for futuredisease development can be reasonably determined.The clear explanation of risk allows for effective indi-vidual counseling regarding personal choice and theability to screen and explain the significance for testingamong family members. Because of limited humanstudies adequately powered to calculate disease riskassociated with epigenetic alterations and subsequentcircumscribed availability of screening biomarkers,there may be limited information to support informedclinical decision making. Large-scale studies ofepigenome-wide association study data are needed tovalidate epigenetic observations, but this also requiresattention in the regulatory area to protect patientprivacy and allow the state of the science to moveforward. The current challenge to understand theimplications of epigenetic alterations in developmentand disease may limit nurses’ effectiveness in theprovision of education and counseling that is of clinicaluse, hindering the ability to make better health deci-sions among individuals and families (Badzek et al.,2012).

Ethical, Legal, and Socioeconomic Policy Implications

Awareness of the social, legal, ethical, and economicissues associated with DNA methylation is increasingand has relevance for research, practice, and publicpolicy (Badzek et al., 2012). The influence of environ-mental factors (toxins, diet, stress, exercise, smoking,alcohol drugs, pathogens, and temperature) on DNAmethylation can lead to altered phenotype, diseasesusceptibility, stress response, behavior, and longevity(Kargul & Laurent, 2009; Tammen, Friso, & Choi, 2012;F. F. Zhang et al., 2011). There is also an increasedlikelihood of exposure to epigenetic modifiers inpopulations of lower socioeconomic status, whichmay increase vulnerability to epigenomic disruption(Lundborg & Stenberg, 2010; Rothstein, Cai, &Marchant, 2009a). Stress, poor nutrition, substandardliving conditions, and reduced access to preventive

Nur s Out l o o k 6 1 ( 2 0 1 3 ) 2 3 5e 2 4 1240

health care are often associated with poverty and havethe potential to independently alter the epigenome,leading to increased vulnerability to additional expo-sure of environmental epigenetic modifiers (Rothstein,Cai, & Marchant, 2009a).

Environmental regulations designed to limit expo-sure to substances including pollutants, chemicals,and certain metals are emerging, with recommenda-tions for lower acceptable exposure levels for youngchildren. Although these regulations do not cite expo-sure risks specifically associated with changes in DNAmethylation (Milagro, Mansego, De Miguel, & Martinez,2012), the mechanisms of actions and timing at criticalpoints during development suggest an epigenetic basisfor health consequences secondary to environmentalexposures (Rothstein, Cai, & Marchant, 2009b). There isconsiderable debate surrounding the establishment ofregulations mandating screening for the effects ofepigenetic modifiers, indicative of challenges address-ing the direct influence of environmental substanceson the epigenome. In light of the transgenerationaleffect of some epigenomic modifications resultingfrom environmental exposures, the legal andfinancial implications are staggering as first manifes-tations of disease may occur one or more generationsafter initial exposure (Rothstein, Cai, & Marchant,2009a).

The environmental challenges to epigenetic modifi-cations present a threat to public health, particularlyamong those most vulnerable. Maternalechild healthpolicies that promote optimal maternal, fetal, andinfant well-being through avoidance of environmentalepigeneticmodifiershave thepotential to impacthealthacross multiple generations (Lundborg & Stenberg,2010). Policy implications for epigenetics and pediatrichealth research include clear expectations that productsafety and cumulative health risks and benefits areestablished and communicated, promoting pediatrichealth and the health of the population as a whole(Witherspoon, Trousdale, Bearer, & Miller, 2012).

Protection of health information is also an impor-tant consideration in epigenetics research and requiresforesight by scientists for two primary reasons. First,research findings could reveal the heightened risk ofdisease in the individual tested and the potential forheritable risk affecting family members. Second,knowledge development in epigenomics is increasingat a pace faster than our ability to set policy to guideappropriate application in research and practice.Outcomes of the sharing of “-omic” high-throughputdata include advancement in scientific developmentand heightened concerns regarding protection of theinterests of participants who provided the biologicalsamples (Ayuso et al., 2013; Haga & O’Daniel, 2011;Rodriguez, Brooks, Greenberg, & Green, 2013). Thepotential of matching an epigenome profile to anindividual underscores the importance of protectingprivate information through policy generation for theuse of epigenomic data in research and practice(Schmidt & Callier, 2012).

The issues of ownership and sharing of data, returnof results, misconceptions regarding a therapeuticoutcomeof testing, and incidental findings arebut a fewof the ethical considerations in epigenomic research(Henderson, Juengst, King, Kuczynski, & Michie, 2012).The availability of individual epigenomic data has thepotential for use in clinical practice, serving as the basisfor personalized strategies for prevention, prediction,and treatment of disease (Shublaq & Coveney, 2012). Tomaximize this capability, large databases that holdgenomic information must interact with individualelectronic health record data (Shublaq&Coveney 2012).The repository and clinical application of epigeneticinformation can be modeled after other systems thatare in use and developed for genome-wide associationstudy, designed to incorporate genomic informationinto routine health care delivery (McCarty et al., 2011).Although concerns regarding privacy of healthinformation have been identified, policy developmentto assure confidentiality is not yet fully developed(Kaye, 2012).

The establishment of policy to guide the study andapplication of DNA methylation is a consequence ofthe ability of environmental factors to alter theepigenome, establishing the mechanisms for diseasedevelopment. Conversely, knowledge of gene expres-sion through DNA methylation manipulation repre-sents the potential for prevention and treatment ofdisease (Cleeren, Van der Heyden, Brand, & Van Oyen,2011), the key approaches that impact nursing scienceand practice. The dynamic nature of knowledgeevolution in epigenetics requires competency devel-opment at all levels of nursing education (Kirk,Calzone, Arimori, & Tonkin, 2011) and practice(Howington, Riddlesperger, & Cheek, 2011; Jenkins,2011; Johnson, Giarelli, Lewis, & Rice, 2012; Powell,Hasegawa, & McWalter, 2010; Prows & Saldana, 2009;Santos et al., 2013; Snyder, 2011; Williams et al., 2011).Nurses are uniquely positioned to serve as key playersas epigenetic research advances. The heritability,increased susceptibility in early development, persis-tence of alterations through the life span, and thereversible nature of epigenetic modification suggestcharacteristics that are amenable to nursing interven-tion, mitigating pathology.

Conclusion

Investigation of DNA methylation patterns related tocomplex disease processes has the potential to identifybiological mechanisms that contribute to the devel-opment of disease. Overall, geneeenvironment inter-action models are useful for guiding researchinvestigating DNA methylation patterns because itallows for a holistic approach. DNA methylationpatterns are readily measurable and offer insight intohow environmental interaction can impact health bycausing changes in gene expression.

Nur s Ou t l o o k 6 1 ( 2 0 1 3 ) 2 3 5e 2 4 1 241

The need for translation of the basic science toclinical care will require engagement with populations,application of ethical principles, and research to iden-tify best practices in the application of epigeneticfindings in research and practice across the life span(Barouki, Gluckman, Grandjean, Hanson, & Heindel,2012). Nurse scientists must extend their knowledgebeyond genetic alterations, embracing the investiga-tion and translation of epigenetics in complex diseaseprevention, screening, diagnosis, and treatment(Calzone et al., 2010; Calzone et al., 2011; Conley et al.,2013). Nursing’s emphasis on the ethical, legal, andsocial implications in genomics provides the templatefor application to epigenomics, particularly in relationto application of ethical principles and facilitating

ethical decision. Nurses are adept at developingresearch and health care policy for effective imple-mentation strategies that are congruent with client’svalues and beliefs (Greco et al., 2012). Nurses havea unique opportunity to identify and implementpersonalized interventions that result from translationof DNA methylation research.

References

Available in the online version of this article at theNursing Outlook Website: www.nursingoutlook.org.

r e f e r e n c e s

Anderson, C. M., Ralph, J. L., Wright, M. L., Linggi, B., & Ohm, J. E.(2013). DNA methylation as a biomarker for preeclampsia. BiolRes Nurs, In Press.

Anderson, O. S., Nahar, M. S., Faulk, C., Jones, T. R., Liao, C.,Kannan, K., & Dolinoy, D. C. (2012). Epigenetic responsesfollowing maternal dietary exposure to physiologicallyrelevant levels of bisphenol A. Environ Mol Mutagenesis, 53(5),334e342. http://dx.doi.org/10.1002/em.21692.

Anderson, O. S., Sant, K. E., & Dolinoy, D. C. (2012). Nutrition andepigenetics: An interplay of dietary methyl donors, one-carbon metabolism and DNA methylation. J Nutr Biochem,23(8), 853e859. http://dx.doi.org/10.1016/j.jnutbio.2012.03.003.

Archer, T., Oscar-Berman, M., Blum, K., & Gold, M. (2012).Neurogenetics and epigenetics in impulsive behaviour: Impacton reward circuitry. J Genet Syndr Gene Ther, 3(3), 1000115.http://dx.doi.org/10.4172/2157-7412.1000115.

Ayuso, C., Millan, J. M., Mancheno, M., & Dal-Re, R. (2013).Informed consent for whole-genome sequencing studies inthe clinical setting. Proposed recommendations on essentialcontent and process. Eur J Hum Genet EJHG, http://dx.doi.org/10.1038/ejhg.2012.297.

Baccarelli, A., Rienstra, M., & Benjamin, E. J. (2010). Cardiovascularepigenetics: Basic concepts and results from animal andhuman studies. Circulation Cardiovasc Genet, 3(6), 567e573.http://dx.doi.org/10.1161/CIRCGENETICS.110.958744.

Badzek, L., Henaghan, M., Turner, M., & Monsen, R. (2012). Ethical,legal, and social issues in the translation of genomics intohealth care. J Nurs Scholarship. http://dx.doi.org/10.1111/jnu.12000, no-no.

Barouki, R., Gluckman, P. D., Grandjean, P., Hanson, M., &Heindel, J. J. (2012). Developmental origins of non-communicable disease: Implications for research and publichealth. Environ Health, 11(42). http://dx.doi.org/10.1186/1476e069X-11-42.

Berger, S. L., Kouzarides, T., Shiekhattar, R., & Shilatifard, A.(2009). An operational definition of epigenetics. Genes Dev,23(7), 781e783. http://dx.doi.org/10.1101/gad.1787609.

Bernal, A. J., & Jirtle, R. L. (2010). Epigenomic disruption: Theeffects of early developmental exposures. Birth Defects ResearchPart A, Clin Mol Teratology, 88(10), 938e944. http://dx.doi.org/10.1002/bdra.20685.

Bi, F. F., Li, D., & Yang, Q. (2013). Promoter hypomethylation,especially around the E26 transformation-specific motif, andincreased expression of poly (ADP-ribose) polymerase 1 inBRCA-mutated serous ovarian cancer. BMC Cancer, 13. http://dx.doi.org/10.1186/1471-2407-13-90, 90-2407-13-90.

Brait, M., Munari, E., Lebron, C., Noordhuis, M. G., Begum, S.,Michailidi, C., & Hoque, M. O. (2013). Genome-widemethylation profiling and the PI3K-AKT pathway analysisassociated with smoking in urothelial cell carcinoma. CellCycle (Georgetown, Tex.), 12(7), 1058e1070. http://dx.doi.org/10.4161/cc.24050.

Brutsaert, T. D., & Parra, E. J. (2006). What makes a champion?Explaining variation in human athletic performance. RespirPhysiol Neurobiol, 151(2-3), 109e123. http://dx.doi.org/10.1016/j.resp.2005.12.013.

Calzone, K. A., Cashion, A., Feetham, S., Jenkins, J., Prows, C. A.,Williams, J. K., & Wung, S. F. (2010). Nurses transforminghealth care using genetics and genomics. Nurs Outlook, 58(1),26e35. http://dx.doi.org/10.1016/j.outlook.2009.05.001.

Calzone, K. A., Jenkins, J., Prows, C. A., & Masny, A. (2011).Establishing the outcome indicators for the essential nursingcompetencies and curricula guidelines for genetics andgenomics. J Prof Nurs Official J Am Assoc Colleges Nurs, 27(3),179e191. http://dx.doi.org/10.1016/j.profnurs.2011.01.001.

Chadwell, K. (2013). Clinical practice on the horizon: Personalizedmedicine. Clin Nurse Specialist CNS, 27(1), 36e43. http://dx.doi.org/10.1097/NUR.0b013e318277703c.

Cheng, H., Deng, Z., Wang, Z., Zhang, W., & Su, J. (2012). MTHFRC677T polymorphisms are associated with aberrantmethylation of the IGF-2 gene in transitional cell carcinoma ofthe bladder. J Biomed Res, 26(2), 77e83. http://dx.doi.org/10.1016/S1674-8301(12)60015-3.

Chouliaras, L., Mastroeni, D., Delvaux, E., Grover, A., Kenis, G.,Hof, P. R., & van den Hove, D. L. (2013). Consistent decrease inglobal DNA methylation and hydroxymethylation in thehippocampus of Alzheimer’s disease patients. Neurobiol Aging,. http://dx.doi.org/10.1016/j.neurobiolaging.2013.02.021.

Chung, W. C., & Auger, A. P. (2013). Gender differences inneurodevelopment and epigenetics. Pflugers Archiv: Eur JPhysiol, http://dx.doi.org/10.1007/s00424-013-1258-4.

Cleeren, E., Van der Heyden, J., Brand, A., & Van Oyen, H. (2011).Public health in the genomic era: Will public healthgenomics contribute to major changes in the prevention ofcommon diseases? Arch Public Health ¼ Arch Belges De SantePublique, 69(1). http://dx.doi.org/10.1186/0778-7367-69-8,8-7367-69-8.

Conley, Y. P., Biesecker, L. G., Gonsalves, S., Merkle, C. J., Kirk, M.,& Aouizerat, B. E. (2013). Current and emerging technologyapproaches in genomics. J Nurs Scholarship: Official Publ SigmaTheta Tau Int Honor Soc Nurs/Sigma Theta Tau, http://dx.doi.org/10.1111/jnu.12001.

Consensus Panel. (2008). In J. Jenkins, & K. Calzone (Eds.),Essentials of Genetic and Genomic Nursing: Competencies, CurriculaGuidelines, and Outcome Indicators (2nd ed.). Bethesda, MD:American Nurses Association.

Consensus Panel. (2011). In K. Greco, S. Tinley, & D. Seibert (Eds.),Essential Genetic and Genomic Competencies for Nurses withGraduate Degrees (2nd ed.). Bethesda, MD: American NursesAssociation.

Cui, H., Horon, I. L., Ohlsson, R., Hamilton, S. R., & Feinberg, A. P.(1998). Loss of imprinting in normal tissue of colorectal cancerpatients with microsatellite instability. Nat Med, 4(11),1276e1280. http://dx.doi.org/10.1038/3260.

Custovic, A., Marinho, S., & Simpson, A. (2012). Gene-environment interactions in the development of asthma andatopy. Expert Rev Respir Med, 6(3), 301e308. http://dx.doi.org/10.1586/ers.12.24.

Davis, C. D., & Uthus, E. O. (2004). DNA methylation, cancersusceptibility, and nutrient interactions. Exp Biol Med(Maywood, N.J.), 229(10), 988e995.

Day, C. P., & James, O. F. (1998). Steatohepatitis: A tale of two"hits"? Gastroenterology, 114(4), 842e845.

Delaney, C., Garg, S. K., Fernandes, C., Hoeltzel, M., Allen, R. H.,Stabler, S., & Yung, R. (2013). Maternal diet supplementedwith methyl-donors protects against atherosclerosis in F1ApoE(�/�) mice. PloS One, 8(2), e56253. http://dx.doi.org/10.1371/journal.pone.0056253.

Detich, N., Bovenzi, V., & Szyf, M. (2003). Valproate inducesreplication-independent active DNA demethylation. J BiolChem, 278(30), 27586e27592. http://dx.doi.org/10.1074/jbc.M303740200.

Ellinger, J., Kahl, P., von der Gathen, J., Rogenhofer, S.,Heukamp, L. C., Gutgemann, I., & von Ruecker, A. (2010).Global levels of histone modifications predict prostate cancerrecurrence. The Prostate, 70(1), 61e69. http://dx.doi.org/10.1002/pros.21038.

Feinberg, A. P. (2008). Epigenetics at the epicenter of modernmedicine. JAMA: J Am Med Assoc, 299(11), 1345e1350. http://dx.doi.org/10.1001/jama.299.11.1345.

Fernandez-Tajes, J., Soto-Hermida, A., Vazquez-Mosquera, M. E.,Cortes-Pereira, E., Mosquera, A., Fernandez-Moreno, M., &Blanco, F. J. (2013). Genome-wide DNA methylation analysis of

Nur s Out l o o k 6 1 ( 2 0 1 3 ) 2 3 5e 2 4 1241.e1

articular chondrocytes reveals a cluster of osteoarthriticpatients. Ann Rheum Dis, http://dx.doi.org/10.1136/annrheumdis-2012-202783.

Franklin, T. B., Russig, H., Weiss, I. C., Graff, J., Linder, N.,Michalon, A., & Mansuy, I. M. (2010). Epigenetic transmission ofthe impact of early stress across generations. Biol Psychiatry,68(5), 408e415. http://dx.doi.org/10.1016/j.biopsych.2010.05.036.

Greco, K. E., Tinley, S., & Seibert, D. (2012). Essential Genetic andGenomic Competencies for Nurses with Graduate Degrees. SilverSpring, MD: American Nurses Association and theInternational Society of Nurses in Genetics.

Grissom, N. M., & Reyes, T. M. (2012). Gestational overgrowth andundergrowth affect neurodevelopment: Similarities anddifferences from behavior to epigenetics. Int J Dev NeurosciOfficial J Int Soc Dev Neurosci, http://dx.doi.org/10.1016/j.ijdevneu.2012.11.006.

Haga, S. B., & O’Daniel, J. (2011). Public perspectives regardingdata-sharing practices in genomics research. Public HealthGenomics, 14(6), 319e324. http://dx.doi.org/10.1159/000324705.

Henderson, G. E., Juengst, E. T., King, N. M., Kuczynski, K., &Michie, M. (2012). What research ethics should learn fromgenomics and society research: Lessons from the ELSIcongress of 2011. J L Med Ethics A J Am Soc L Med Ethics,40(4), 1008e1024. http://dx.doi.org/10.1111/j.1748-720X.2012.00728.x.

Hewagama, A., Gorelik, G., Patel, D., Liyanarachchi, P., JosephMcCune, W., Somers, E., & Richardson, B. (2013). OverexpressionofX-linked genes inT cells fromwomenwith lupus. J Autoimmun,41, 60e71. http://dx.doi.org/10.1016/j.jaut.2012.12.006.

Ho, A. S., Turcan, S., & Chan, T. A. (2013). Epigenetic therapy: Useof agents targeting deacetylation and methylation in cancermanagement. OncoTargets Ther, 6, 223e232. http://dx.doi.org/10.2147/OTT.S34680.

Howington, L., Riddlesperger, K., & Cheek, D. J. (2011). Essentialnursing competencies for genetics and genomics: Implicationsfor critical care. Crit Care Nurse, 31(5), e1ee7. http://dx.doi.org/10.4037/ccn2011867.

Huidobro, C., Fernandez, A. F., & Fraga, M. F. (2013). The role ofgenetics in the establishment and maintenance of theepigenome. Cell Mol Life Sci CMLS, 70(9), 1543e1573. http://dx.doi.org/10.1007/s00018-013-1296-2.

Jenkins, J. (2011). Essential genetic and genomic nursingcompetencies for the oncology nurse. Semin Oncol Nurs, 27(1),64e71. http://dx.doi.org/10.1016/j.soncn.2010.11.008.

Jia, L., Zhu, L., Wang, J. Z., Wang, X. J., Chen, J. Z., Song, L., & Hui, R.(2013). Methylation of FOXP3 in regulatory T cells is related tothe severity of coronary artery disease. Atherosclerosis, http://dx.doi.org/10.1016/j.atherosclerosis.2013.01.027.

Johnson, N. L., Giarelli, E., Lewis, C., & Rice, C. E. (2012). Genomicsand autism spectrum disorder. J Nurs Scholarship. http://dx.doi.org/10.1111/j.1547-5069.2012.01483.x, no-no.

Jones, P. A., & Baylin, S. B. (2002). The fundamental role ofepigenetic events in cancer. Nat Reviews.Genetics, 3(6), 415e428.http://dx.doi.org/10.1038/nrg816.

Kaminskas, E., Farrell, A. T., Wang, Y. C., Sridhara, R., & Pazdur, R.(2005). FDA drug approval summary: Azacitidine (5-azacytidine,vidaza) for injectable suspension. The Oncologist, 10(3), 176e182.http://dx.doi.org/10.1634/theoncologist.10-3-176.

Kargul, J., & Laurent, G. J. (2009). Epigenetics and human disease.Int J Biochem Cell Biol, 41(1), 1. http://dx.doi.org/10.1016/j.biocel.2008.09.017.

Kaye, J. (2012). The tension between data sharing and theprotection of privacy in genomics research. Annu Rev GenomicsHum Genet, 13, 415e431. http://dx.doi.org/10.1146/annurev-genom-082410-101454.

Kendall, A. I. (1915). The bacteria of the intestinal tract of man. Sci(New York, N.Y.), 42(1076), 209e212. http://dx.doi.org/10.1126/science.42.1076.209.

Kim, G. H., Ryan, J. J., & Archer, S. L. (2013). The role of redoxsignaling in epigenetics and cardiovascular disease. AntioxidRedox Signaling, 18(15), 1920e1936. http://dx.doi.org/10.1089/ars.2012.4926.

Kim, R., Kulkarni, P., & Hannenhalli, S. (2013). Derepression ofcancer/testis antigens in cancer is associated with distinctpatterns of DNA hypomethylation. BMC Cancer, 13. http://dx.doi.org/10.1186/1471-2407-13-144, 144-2407-13-144.

Kirchner, S., Kieu, T., Chow, C., Casey, S., & Blumberg, B. (2010).Prenatal exposure to the environmental obesogen tributyltinpredisposes multipotent stem cells to become adipocytes. MolEndocrinol (Baltimore, Md, 24(3), 526e539. http://dx.doi.org/10.1210/me.2009-0261.

Kirk, M., Calzone, K., Arimori, N., & Tonkin, E. (2011). Genetics-genomics competencies and nursing regulation. J NursScholarship: Official Publ Sigma Theta Tau Int Honor Soc Nurs/Sigma Theta Tau, 43(2), 107e116. http://dx.doi.org/10.1111/j.1547-5069.2011.01388.x.

Kirkbride, J. B., Susser, E., Kundakovic, M., Kresovich, J. K., DaveySmith, G., & Relton, C. L. (2012). Prenatal nutrition, epigeneticsand schizophrenia risk: Can we test causal effects?Epigenomics, 4(3), 303e315. http://dx.doi.org/10.2217/epi.12.20.

Kordi-Tamandani, D. M., Dahmardeh, N., & Torkamanzehi, A.(2013). Evaluation of hypermethylation and expression patternof GMR2, GMR5, GMR8, and GRIA3 in patients withschizophrenia. Gene, 515(1), 163e166. http://dx.doi.org/10.1016/j.gene.2012.10.075.

Kordi-Tamandani, D. M., Sahranavard, R., & Torkamanzehi, A.(2012). DNA methylation and expression profiles of the brain-derived neurotrophic factor (BDNF) and dopamine transporter(DAT1) genes in patients with schizophrenia. Mol Biol Rep,39(12), 10889e10893. http://dx.doi.org/10.1007/s11033-012-1986-0.

Latham, K. E., Sapienza, C., & Engel, N. (2012). The epigeneticlorax: Gene-environment interactions in human health.Epigenomics, 4(4), 383e402. http://dx.doi.org/10.2217/epi.12.31.

Lee, B. H., Yegnasubramanian, S., Lin, X., & Nelson, W. G. (2005).Procainamide is a specific inhibitor of DNA methyltransferase1. J Biol Chem, 280(49), 40749e40756. http://dx.doi.org/10.1074/jbc.M505593200.

Lu, D., Dong, D., Zhou, Y., Lu, M., Pang, X. W., Li, Y., & Zhang, J.(2013). The tumor suppressive function of UNC5D and itsrepressed expression in renal cell carcinoma. Clin Cancer ResOfficial J Am Assoc Cancer Res, http://dx.doi.org/10.1158/1078-0432.CCR-12-2978.

Lundborg, P., & Stenberg, A. (2010). Nature, nurture andsocioeconomic policydWhat can we learn from moleculargenetics? Econ Hum Biol, 8(3), 320e330. http://dx.doi.org/10.1016/j.ehb.2010.08.002.

McCarty, C. A., Chisholm, R. L., Chute, C. G., Kullo, I. J.,Jarvik, G. P., Larson, E. B., & eMERGE Team. (2011). TheeMERGE network: A consortium of biorepositories linked toelectronic medical records data for conducting genomicstudies. BMC Med Genomics, 4. http://dx.doi.org/10.1186/1755-8794-4-13, 13-8794-4-13.

Melas, P. A., Rogdaki, M., Osby, U., Schalling, M., Lavebratt, C., &Ekstrom, T. J. (2012). Epigenetic aberrations in leukocytes ofpatients with schizophrenia: Association of global DNAmethylation with antipsychotic drug treatment and diseaseonset. FASEB J Official Publ Fed Am Societies Exp Biol, 26(6),2712e2718. http://dx.doi.org/10.1096/fj.11-202069.

Milagro, F. I., Mansego, M. L., De Miguel, C., & Martinez, J. A.(2012). Dietary factors, epigenetic modifications and obesityoutcomes: Progresses and perspectives. Mol Aspects Med,http://dx.doi.org/10.1016/j.mam.2012.06.010.

Mirza, S., Sharma, G., Parshad, R., Gupta, S. D., Pandya, P., &Ralhan, R. (2013). Expression of DNA methyltransferases inbreast cancer patients and to analyze the effect of natural

Nur s Ou t l o o k 6 1 ( 2 0 1 3 ) 2 3 5e 2 4 1 241.e2

compounds on DNA methyltransferases and associatedproteins. J Breast Cancer, 16(1), 23e31. http://dx.doi.org/10.4048/jbc.2013.16.1.23.

National Coalition for Health Professional Education in GeneticsSteering Committee. (2007). Core Competencies in Genetics forHealth Professionals (3rd ed.).

Nelson, W. G., De Marzo, A. M., & Yegnasubramanian, S. (2009).Epigenetic alterations in human prostate cancers.Endocrinology, 150(9), 3991e4002. http://dx.doi.org/10.1210/en.2009-0573.

NIEHS, National Institute of Environmental Health Sciences.(2012). Gene-Environment Interaction. Retrieved February 4, 2013,from. http://www.niehs.nih.gov/health/topics/science/gene-env/index.cfm.

Nishioka, M., Bundo, M., Koike, S., Takizawa, R., Kakiuchi, C.,Araki, T., & Iwamoto, K. (2013). Comprehensive DNAmethylation analysis of peripheral blood cells derived frompatients with first-episode schizophrenia. J Hum Genet, 58(2),91e97. http://dx.doi.org/10.1038/jhg.2012.140.

Olszak, T., An, D., Zeissig, S., Vera, M. P., Richter, J., Franke, A., &Blumberg, R. S. (2012). Microbial exposure during early life haspersistent effects on natural killer T cell function. Sci (NewYork, N.Y.), 336(6080), 489e493. http://dx.doi.org/10.1126/science.1219328.

Ostrow, K., Michailidi, C., Guerrero-Preston, R., Greenberg, A.,Rom, W., Sidransky, D., & Hoque, M. (2013). Cigarette smokeinduces methylation of the tumor suppressor gene NISCH.Epigenetics: Official J DNA Methylation Soc, 8(4).

Patel, D. R., & Richardson, B. C. (2013). Dissecting complexepigenetic alterations in human lupus. Arthritis Res Ther, 15(1),201. http://dx.doi.org/10.1186/ar4125.

Philibert, R. A., Beach, S. R., & Brody, G. H. (2012). Demethylationof the aryl hydrocarbon receptor repressor as a biomarker fornascent smokers. Epigenetics: Official J DNA Methylation Soc,7(11), 1331e1338. http://dx.doi.org/10.4161/epi.22520.

Powell, K. P., Hasegawa, L., & McWalter, K. (2010). Expandingroles: A survey of public health genetic counselors. J GenetCouns, 19(6), 593e605. http://dx.doi.org/10.1007/s10897-010-9313-1.

Prows, C. A., & Saldana, S. N. (2009). Nurses’ genetic/genomicscompetencies when medication therapy is guided bypharmacogenetic testing: Children with mental healthdisorders as an exemplar. J Pediatr Nurs, 24(3), 179e188. http://dx.doi.org/10.1016/j.pedn.2008.02.033.

Rodenhiser, D., & Mann, M. (2006). Epigenetics and humandisease: Translating basic biology into clinical applications.CMAJ: Can Med Assoc J ¼ J De l’Association Medicale Canadienne,174(3), 341e348. http://dx.doi.org/10.1503/cmaj.050774.

Rodriguez, L. L., Brooks, L. D., Greenberg, J. H., & Green, E. D.(2013). Research ethics. The complexities of genomicidentifiability. Sci (New York, N.Y.), 339(6117), 275e276. http://dx.doi.org/10.1126/science.1234593.

Rodriguez-Paredes, M., & Esteller, M. (2011). Cancer epigeneticsreaches mainstream oncology. Nat Med, 17(3), 330e339. http://dx.doi.org/10.1038/nm.2305.

Rothstein, M. A., Cai, Y., & Marchant, G. E. (2009a). Ethicalimplications of epigenetics research. Nat Reviews.Genetics,10(4), 224. http://dx.doi.org/10.1038/nrg2562.

Rothstein, M. A., Cai, Y., & Marchant, G. E. (2009b). The ghost inour genes: Legal and ethical implications of epigenetics. HealthMatrix (Cleveland, Ohio: 1991), 19(1), 1e62.

Sanchis-Gomar, F., Garcia-Gimenez, J. L., Perez-Quilis, C., Gomez-Cabrera, M. C., Pallardo, F. V., & Lippi, G. (2012). Physicalexercise as an epigenetic modulator: Eustress, the "positivestress" as an effector of gene expression. J Strength ConditioningRes/Natl Strength Conditioning Assoc, 26(12), 3469e3472. http://dx.doi.org/10.1519/JSC.0b013e31825bb594.

Santos, E. M., Edwards, Q. T., Floria-Santos, M., Rogatto, S. R.,Achatz, M. I., & Macdonald, D. J. (2013). Integration ofgenomics in cancer care. J Nurs Scholarship: Official Publ SigmaTheta Tau Int Honor Soc Nurs/Sigma Theta Tau, http://dx.doi.org/10.1111/j.1547-5069.2012.01465.x.

Sawalha, A. H., Wang, L., Nadig, A., Somers, E. C., McCune, W. J.,Michigan Lupus Cohort, & Richardson, B. (2012). Sex-specificdifferences in the relationship between genetic susceptibility,T cell DNA demethylation and lupus flare severity.J Autoimmun, 38(2-3), J216eJ222. http://dx.doi.org/10.1016/j.jaut.2011.11.008.

Schmidt, H., & Callier, S. (2012). How anonymous is ’anonymous’?Some suggestions towards a coherent universal codingsystem for genetic samples. J Med Ethics, 38(5), 304e309. http://dx.doi.org/10.1136/medethics-2011-100181.

Seisenberger, S., Peat, J. R., & Reik, W. (2013). Conceptual linksbetween DNA methylation reprogramming in the earlyembryo and primordial germ cells. Curr Opin Cell Biol, http://dx.doi.org/10.1016/j.ceb.2013.02.013.

Shublaq, N. W., & Coveney, P. V. (2012). Merging genomic andphenomic data for research and clinical impact. Stud HealthTechnol Inform, 174, 111e115.

Singh, S., & Li, S. S. (2012). Epigenetic effects of environmentalchemicals bisphenol A and phthalates. Int J Mol Sci, 13(8),10143e10153. http://dx.doi.org/10.3390/ijms130810143.

Snyder, C. (2011). Genetic information and discrimination: Apolicy analysis. Clin J Oncol Nurs, 15(3), 330e332. http://dx.doi.org/10.1188/11.CJON.330-332.

Starkman, B. G., Sakharkar, A. J., & Pandey, S. C. (2012).EpigeneticsdBeyond the genome in alcoholism. Alcohol ResCurr Rev, 34(3), 293e305.

Strickland, F. M., Hewagama, A., Wu, A., Sawalha, A. H.,Delaney, C., Hoeltzel, M. F., & Richardson, B. C. (2013). Dietinfluences expression of autoimmune associated genes anddisease severity by epigenetic mechanisms in a transgeniclupus model. Arthritis Rheum, http://dx.doi.org/10.1002/art.37967.

Tammen, S. A., Friso, S., & Choi, S. W. (2012). Epigenetics: The linkbetween nature and nurture. Mol Aspects Med, . http://dx.doi.org/10.1016/j.mam.2012.07.018.

Tang, W., Li, B., Tang, J., Liu, K., Qin, J., Wu, W., & Xia, Y. (2013).Methylation analysis of EDNRB in human colon tissues ofHirschsprung’s disease. Pediatr Surg Int, . http://dx.doi.org/10.1007/s00383-013-3308-6.

Waring, R. H., & Harris, R. M. (2011). Endocrine disruptersdAthreat to women’s health? Maturitas, 68(2), 111e115. http://dx.doi.org/10.1016/j.maturitas.2010.10.008.

Waterland, R. A., Dolinoy, D. C., Lin, J. R., Smith, C. A., Shi, X., &Tahiliani, K. G. (2006). Maternal methyl supplements increaseoffspring DNA methylation at axin fused. Genesis (New York,N.Y.: 2000), 44(9), 401e406. http://dx.doi.org/10.1002/dvg.20230.

Weiss, I. C., Franklin, T. B., Vizi, S., & Mansuy, I. M. (2011).Inheritable effect of unpredictable maternal separation onbehavioral responses in mice. Front Behav Neurosci, 5, 3. http://dx.doi.org/10.3389/fnbeh.2011.00003.

Wijermans, P. W., Lubbert, M., Verhoef, G., Klimek, V., & Bosly, A.(2005). An epigenetic approach to the treatment of advancedMDS; the experience with the DNA demethylating agent 5-aza-20-deoxycytidine (decitabine) in 177 patients. Ann Hematol,84(Suppl 1), 9e17. http://dx.doi.org/10.1007/s00277-005-0012-1.

Williams, J. K., Prows, C. A., Conley, Y. P., Eggert, J., Kirk, M., &Nichols, F. (2011). Strategies to prepare faculty to integrategenomics into nursing education programs. J Nurs Scholarship:Official Publ Sigma Theta Tau Int Honor Soc Nurs/Sigma Theta Tau,43(3), 231e238. http://dx.doi.org/10.1111/j.1547-5069.2011.01401.x.

Nur s Out l o o k 6 1 ( 2 0 1 3 ) 2 3 5e 2 4 1241.e3

Witherspoon, N. O., Trousdale, K., Bearer, C. F., & Miller, R. L.(2012). The public health and policy implications ofepigenetics and pediatric health research. Environ HealthPerspect, 120(10), a380ea381. http://dx.doi.org/10.1289/ehp.1205956.

Xu, H., Wang, B., Su, D., Yu, Q., Li, Q., Kou, C., & Ma, X. (2012). TheDNA methylation profile of PLA2G4C gene promoter inschizophrenia. Psychiatry Res, 200(2-3), 1079e1081. http://dx.doi.org/10.1016/j.psychres.2012.07.003.

Yang, B., Bhusari, S., Kueck, J., Weeratunga, P., Wagner, J.,Leverson, G., & Jarrard, D. F. (2013). Methylation profilingdefines an extensive field defect in histologically normalprostate tissues associated with prostate cancer. Neoplasia(New York, N.Y.), 15(4), 399e408.

Zambrano, P., Segura-Pacheco, B., Perez-Cardenas, E.,Cetina, L., Revilla-Vazquez, A., Taja-Chayeb, L., & Duenas-Gonzalez, A. (2005). A phase I study of hydralazine to

demethylate and reactivate the expression of tumorsuppressor genes. BMC Cancer, 5, 44. http://dx.doi.org/10.1186/1471-2407-5-44.

Zhang, F. F., Morabia, A., Carroll, J., Gonzalez, K., Fulda, K.,Kaur, M., & Cardarelli, R. (2011). Dietary patterns areassociated with levels of global genomic DNA methylation ina cancer-free population. J Nutr, 141(6), 1165e1171. http://dx.doi.org/10.3945/jn.110.134536.

Zhang, Y., Li, Q., & Chen, H. (2013). DNA methylation and histonemodifications of wnt genes by genistein during colon cancerdevelopment. Carcinogenesis, http://dx.doi.org/10.1093/carcin/bgt129.

Zhao, Y., Zhou, H., Ma, K., Sun, J., Feng, X., Geng, J., & Lin, Q.(2013). Abnormal methylation of seven genes and theirassociations with clinical characteristics in early stage non-small cell lung cancer. Oncol Lett, 5(4), 1211e1218. http://dx.doi.org/10.3892/ol.2013.1161.

Nur s Ou t l o o k 6 1 ( 2 0 1 3 ) 2 3 5e 2 4 1 241.e4