Subpopulation Aberrant Epigenomic Modulations in Evolutionary Public Health Optimization and Health Equity Transformation

Laurens Holmes, Jr, Principal Translational Epigenomist

Global Health Equity Foundation, GHEF (USA)

Introduction

Currently, racial/ethnic minorities health outcomes remains a substantial explanation of the USA ranking low with respect to global health outcomes. Specifically of all the industrialized nation in the world, US ranks low with respect to infant mortality, maternal mortality and life expectancy. The observed marginalized outcomes in the USA, comparing Japan, Italy, Scandinavians, etc. requires our understanding of how environment related to racial/ethnic monitories predispose to disease incidence, morbidity, impaired prognosis, excess mortality and survival disadvantage, except Asian and Pacific islanders, with the best outcome of health, relative to their white counterparts except the underserved whites. ??

?Aberrant epigenomic modulation, implying the ?gene and environment interaction in a specific population reflects gene downregulation, impaired protein synthesis and cellular dysfunctionality as abnormal cellular proliferation. ?For instance, the individual treatment effect heterogeneity and the subpopulation differences in drug response as observed in decreased response of Puerto Rican children with asthma to Albuterol, ?compared? to Mexicans is due to Single Nucleotide Polymorphism (SNP) in the beta-adrenergic receptor? as well as socially disadvantaged neighborhood, implying subpopulation variances in epigenomic modulation. While precision medicine (PM) initiative emerges as an attempt to address these treatment heterogeneities. The direction of this initiative in the history of medicine will depend not only on specific risk characterization and targeted therapeutics but on how PM optimizes care through preventive modalities, namely “normo-epigenomic modulation” (“NEM”) through everyday equitable resources allocation pertaining to human health.

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Epigenomic Modulation and Precession Medicine Initiative

Medicine as an art and science is imprecise and inexact due in part? to individual treatment response/effect heterogeneity, implying environmental variabilities in morbidity, mortality and survival. The ongoing PM initiative? requires the understanding of the cause of causes ?as epigenomic determinants of health (EDH) such as Social determinants of health (SDH), cytogenetics, SDH-gene interaction, epigenetics), prior to therapeutics. Such attempt at specific risk characterization (individual and subpopulations levels) and induction therapy will involve appropriately designed studies in avoiding reverse causation, adequate analysis and interpretation, studies replication, analogy, dose-response effect size and magnitude of effect in genomic, epigenomic and socio-epigenomic aberrations/lesions as the cause of causes of individual and subpopulations treatment effect heterogeneity

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Nature remains extremely coherent and nothing is self-evident. Patient care improvement requires the uncovering of this coherency through reliable and valid research for evidence discovery by translating findings to therapeutics. This observation is reliable as illustrated in immune system responsiveness to tumor-specific antigen (TSA), where the immune response is switched off and malignancies progresses to metastasis and subsequent mortality, implying the discovery of the progressive turn-on switch, given TSA bio-availability – tumor specific immunotherapy, a direction we are currently conceptualizing.?

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Simply, the understanding of epigenomic modulation and protein synthesis is indicative of how drug response varies by some subpopulations or individual patients. Simply, epigenomic modulations as a mechanistic process involves DNA methylation, histone modification and non-coding RNA; which allows for DNA methylation, histone acetylation, phosphorylation and methylation, etc. For example the DNA methylation requires the binding of the methyl group (CH3) to the C-p-G region of the enhancer region of the gene, resulting in CH3-Cytosine, hence transcriptomes down regulation, impaired gene expression and protein synthesis marginalization, hence cellular dysfunctionality. Since human cells have a status of replication and apoptosis, aberrant epigenomic modulations inversely affects amino acid elaboration as the building blocks of proteins, adversely impacting cell division, differentiation and maturation.??

Epigenetics (epigenome) emerged in 1942 by C.H.Waddington, as? a? study of the process by which genotype (genome) induces phenotype. Specifically, epigenetics heritable changes in gene expression, that do not implicate or reflect changes or alterations in the underlying DNA sequence. As initially observed,? epigenomic modulation involved DNA methylation, histone modification and non-coding RNA. These modifications impacts chromatin conformation, gene expression regulation, as well as transcription factors, coactivators and co-repressors accessibility. Simply, the DNA methylation occurs at the promoter and enhancer region of the gene, especially the carbon-5 of the cytosine in the 5’-C-phosphate –G-3’ (CpG) dinulceotides, which is catalyzed by DNA methyltransferease. This process involves the transfer of methyl group (CH3)? from 5-adenosyl-methione to previously unmethylated cytosines at the promoter region of the gene.

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Racial/ethnic Minorities Disproportionate Burden of Disease: Epigenomics

Racial and ethnic disparities in disease development and health outcomes reflect fundamentally the exposure effect or function of socio-epigenomics, implying gene-social environment interaction that influences rapid response to cellular injury or damage(plasticity),? and not sub-population genetic or cytogenetic differentials, given < 0.05% genetic heterogeneity in genomic subpopulations characterization.

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Medicine and Public Health Trajectory in Aberrant Epigenomic Modulation and Human Health

Medicine and public health remain to address this challenge, epigenomic determinants of health (EDH) as well as social determinants of health ?that is driven by social and health inequity in health disparities including malignant neoplasm incidence and mortality gap narrowing and subsequent elimination in the United States, requiring health equity now.

Specifically, social signal transduction (SST)? due to isolation, social stressor or discrimination reflects the fight or flight notion of the sympathetic nervous system by the elaboration of norepinephrine and the beta adrenergic receptors activation. Mainly, adverse social environment serve as triggers of neural and endocrine responses, influencing cellular response system, resulting in the activation of the intracellular? signal transduction pathways and the subsequent repression or activation of transcription factors that are involved in the transcription of gene bearing response element (GBRE).? This direction implies aberrant epigenomic modulations that adversely impact health outcomes in a specific population predisposed impaired EDH and SDH, with SDH as a component of EDH

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Summary and Recommendations

This brief overview of the contributory effect of epigenomic determinants of health (EDH)and social determinants of health as a component of EDH, as environment in gene interactions, remains a viable perspective in racial/ethnic health disparities understanding and explanation. With this observation, there is a need for public health, biomedical and clinical investigators to continue with the understanding of how DNA methylation and histone modification alters gene expression, resulting in impaired protein synthesis and cellular dysfunctionality, hence disproportionate burden of disease, indicative of disproportionate universalism in health equity transformation nationally and globally.

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