Epigenome-wide association study of total nicotine equivalents in multiethnic current smokers from three prospective cohorts.

The impact of tobacco exposure on health varies by race and ethnicity and is closely tied to internal nicotine dose, a marker of carcinogen uptake. DNA methylation is strongly responsive to smoking status and may mediate health effects, but study of associations with internal dose is limited. We performed a blood leukocyte epigenome-wide association study (EWAS) of urinary total nicotine equivalents (TNEs; a measure of nicotine uptake) and DNA methylation measured using the MethylationEPIC v1.0 BeadChip (EPIC) in six racial and ethnic groups across three cohort studies. In the Multiethnic Cohort Study (discovery, n = 1994), TNEs were associated with differential methylation at 408 CpG sites across >250 genomic regions (p < 9 × 10-8). The top significant sites were annotated to AHRR, F2RL3, RARA, GPR15, PRSS23, and 2q37.1, all of which had decreasing methylation with increasing TNEs. We identified 45 novel CpG sites, of which 42 were unique to the EPIC array and eight annotated to genes not previously linked with smoking-related DNA methylation. The most significant signal in a novel gene was cg03748458 in MIR383;SGCZ. Fifty-one of the 408 discovery sites were validated in the Singapore Chinese Health Study (n = 340) and the Southern Community Cohort Study (n = 394) (Bonferroni corrected p < 1.23 × 10-4). Significant heterogeneity by race and ethnicity was detected for CpG sites in MYO1G and CYTH1. Furthermore, TNEs significantly mediated the association between cigarettes per day and DNA methylation at 15 sites (average 22.5%-44.3% proportion mediated). Our multiethnic study highlights the transethnic and ethnic-specific methylation associations with internal nicotine dose, a strong predictor of smoking-related morbidities.

Small Nucleus Accumbens and Large Cerebral Ventricles in Infants and Toddlers Prior to Receiving Diagnoses of Autism Spectrum Disorder.

Early interventions for autism spectrum disorder (ASD) are increasingly available, while only 42-50% of ASD children are diagnosed before 3 years old (YO). To identify neuroimaging biomarkers for early ASD diagnosis, we evaluated surface- and voxel-based brain morphometry in participants under 3YO who were later diagnosed with ASD. Magnetic resonance imaging data were retrospectively obtained from patients later diagnosed with ASD at Boston Children's Hospital. The ASD participants with comorbidities such as congenital disorder, epilepsy, and global developmental delay/intellectual disability were excluded from statistical analyses. Eighty-five structural brain magnetic resonance imaging images were collected from 81 participants under 3YO and compared with 45 images from 45 gender- and age-matched nonautistic controls (non-ASD). Using an Infant FreeSurfer pipeline, 236 regionally distributed measurements were extracted from each scan. By t-tests and linear mixed models, the smaller nucleus accumbens and larger bilateral lateral, third, and fourth ventricles were identified in the ASD group. Vertex-wise t-statistical maps showed decreased thickness in the caudal anterior cingulate cortex and increased thickness in the right medial orbitofrontal cortex in ASD. The smaller bilateral accumbens nuclei and larger cerebral ventricles were independent of age, gender, or gestational age at birth, suggesting that there are MRI-based biomarkers in prospective ASD patients before they receive the diagnosis and that the volume of the nucleus accumbens and cerebral ventricles can be key MRI-based early biomarkers to predict the emergence of ASD.

The Mauli Ola Study: A Unique Academic-Community Partnership With MA'O Organic Farms to Understand and Address Health Inequities Among Native Hawaiians and Other Pacific Islanders in Hawai'i.

Indigenous peoples, including Native Hawaiians and Pacific Islanders (NHPIs), experience significant cardiometabolic health disparities arising in large part from rapid changes to their diets and food systems. Innovative food sovereignty initiatives led by NHPIs are needed to address these disparities. This article describes a community-based participatory research study that incorporates social and biological measures to examine the impact of an Indigenous-led land-based food sovereignty youth leadership program on health disparities among NHPI youth in Hawai'i. Grounded in the Indigenous knowledge that holistic health and wellbeing of people is inseparable from that of the environment and to counter rampant food insecurity in their community of Wai'anae, O'ahu, MA'O Organic Farms developed a Youth Leadership Training (YLT) program that offers education, nutrition, physical activity, and access to health care. The program also engages YLT interns and their social networks in health education and research in the ongoing Mauli Ola study. Preliminary data from this study affirm the need to address the disproportionately high rates of obesity, type 2 diabetes mellitus (T2D), and poor mental health conditions among young NHPIs in the Wai'anae community, and how the YLT program may provide an effective approach to address this need. Our unique academic-community partnership underscores the importance of social and biomedical research to understand health disparities in the NHPI population, which present novel avenues to enable disease prevention. The outcomes of the Mauli Ola study may serve as a valuable model for health disparities research while leveraging ongoing social programs that support Indigenous food sovereignty.

Vaccine-Associated Shifts in SARS-CoV-2 Infectivity Among the Native Hawaiian and Other Pacific Islander Population in Hawaii.

Native Hawaiians and other Pacific Islanders (NHPIs) across the country have experienced significant disparities because of the COVID-19 pandemic. The Pacific Alliance Against COVID-19 used a community-based participatory approach involving academic and community partners to expand sustainable COVID-19 testing capacity and mitigate the severe consequences among NHPI communities in Hawaii. We describe the approach of this one-year study, some of the results, and how the data are being used to inform next steps for the communities. Clinical Trials.gov identifier: NCT04766333. (Am J Public Health. 2022;112(S9):S896-S899. https://doi.org/10.2105/AJPH.2022.306973).

Adherence to Mediterranean diet impacts gastrointestinal microbial diversity throughout pregnancy.

BACKGROUND: Consumption of a diet with high adherence to a Mediterranean diet pattern (MDP) has been associated with a favorable gastrointestinal tract (GIT) microbiome. A healthy GIT microbiome in pregnancy, as defined by increased alpha diversity, is associated with lower chance of adverse perinatal outcomes. This study aimed to evaluate the impact of adherence to an MDP on GIT microbial diversity longitudinally throughout pregnancy. METHODS: Adherence to MDP was scored by the Alternate Mediterranean (aMED) Diet Quality Score, after being applied to a validated Food Frequency Questionnaire. Association of aMED Scores with GIT alpha diversity profiles were compared linearly and across time using a linear mixed model, including covariates of age, body mass index (BMI), ethnicity, and parity. RESULTS: Forty-one participants of Filipino, Japanese, Native Hawaiian, and Non-Hispanic White descent provided dietary information and microbiome samples during each trimester of pregnancy. Alpha diversity profiles changed over gestation, with decreased microbial diversity in the third trimester. aMED scores positively correlated with Chao1 Index and Observed Species Number (r = 0.244, p = 0.017, and r = 0.233, p = 0.023, respectively). The strongest association was detected in the third trimester (Chao 1: r = 0.43, p = 0.020, Observed Species Number: r = 0.41, p = 0.026). Participants with higher aMED scores had higher relative abundance of Acidaminoacaeae at the family level (p = 0.0169), as well as higher abundance of several species known to increase production of short chain fatty acids within the GIT. CONCLUSIONS: Adherence to MDP pattern is associated with increased maternal GIT microbial diversity, and promotes the abundance of bacteria that produce short chain fatty acids. Increased consumption of fruits, vegetables and legumes with low red meat consumption were key components driving this association. The effect of nutrition however, was less of an effect than pregnancy itself. Further studies are needed to determine if adherence to a Mediterranean diet translates not only into microbial health, but also into reduced risk of adverse pregnancy outcomes.

Genome-wide epigenetic analyses in Japanese immigrant plantation workers with Parkinson's disease and exposure to organochlorines reveal possible involvement of glial genes and pathways involved in neurotoxicity.

BACKGROUND: Parkinson's disease (PD) is a disease of the central nervous system that progressively affects the motor system. Epidemiological studies have provided evidence that exposure to agriculture-related occupations or agrichemicals elevate a person's risk for PD. Here, we sought to examine the possible epigenetic changes associated with working on a plantation on Oahu, HI and/or exposure to organochlorines (OGC) in PD cases. RESULTS: We measured genome-wide DNA methylation using the Illumina Infinium HumanMethylation450K BeadChip array in matched peripheral blood and postmortem brain biospecimens in PD cases (n = 20) assessed for years of plantation work and presence of organochlorines in brain tissue. The comparison of 10+ to 0 years of plantation work exposure detected 7 and 123 differentially methylated loci (DML) in brain and blood DNA, respectively (p < 0.0001). The comparison of cases with 4+ to 0-2 detectable levels of OGCs, identified 8 and 18 DML in brain and blood DNA, respectively (p < 0.0001). Pathway analyses revealed links to key neurotoxic and neuropathologic pathways related to impaired immune and proinflammatory responses as well as impaired clearance of damaged proteins, as found in the predominantly glial cell population in these environmental exposure-related PD cases. CONCLUSIONS: These results suggest that distinct DNA methylation biomarker profiles related to environmental exposures in PD cases with previous exposure can be found in both brain and blood.

Conserved role of intragenic DNA methylation in regulating alternative promoters.

Although it is known that the methylation of DNA in 5' promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear. In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5' CpG island (CGI) promoters, whereas a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences. Tissue-specific intragenic methylation might reduce, or, paradoxically, enhance transcription elongation efficiency. Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes. To investigate the role of intragenic methylation, we generated a map of DNA methylation from the human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were shown to be in intragenic and intergenic regions, whereas less than 3% of CpG islands in 5' promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters. The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue- and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.

Methylation of histone H3 on lysine 79 associates with a group of replication origins and helps limit DNA replication once per cell cycle.

Mammalian DNA replication starts at distinct chromosomal sites in a tissue-specific pattern coordinated with transcription, but previous studies have not yet identified a chromatin modification that correlates with the initiation of DNA replication at particular genomic locations. Here we report that a distinct fraction of replication initiation sites in the human genome are associated with a high frequency of dimethylation of histone H3 lysine K79 (H3K79Me2). H3K79Me2-containing chromatin exhibited the highest genome-wide enrichment for replication initiation events observed for any chromatin modification examined thus far (23.39% of H3K79Me2 peaks were detected in regions adjacent to replication initiation events). The association of H3K79Me2 with replication initiation sites was independent and not synergistic with other chromatin modifications. H3K79 dimethylation exhibited wider distribution on chromatin during S-phase, but only regions with H3K79 methylation in G1 and G2 were enriched in replication initiation events. H3K79 was dimethylated in a region containing a functional replicator (a DNA sequence capable of initiating DNA replication), but the methylation was not evident in a mutant replicator that could not initiate replication. Depletion of DOT1L, the sole enzyme responsible for H3K79 methylation, triggered limited genomic over-replication although most cells could continue to proliferate and replicate DNA in the absence of methylated H3K79. Thus, prevention of H3K79 methylation might affect regulatory processes that modulate the order and timing of DNA replication. These data are consistent with the hypothesis that dimethylated H3K79 associates with some replication origins and marks replicated chromatin during S-phase to prevent re-replication and preserve genomic stability.

Lsh, chromatin remodeling family member, modulates genome-wide cytosine methylation patterns at nonrepeat sequences.

DNA methylation is critical for normal development and plays important roles in genome organization and transcriptional regulation. Although DNA methyltransferases have been identified, the factors that establish and contribute to genome-wide methylation patterns remain elusive. Here, we report a high-resolution cytosine methylation map of the murine genome modulated by Lsh, a chromatin remodeling family member that has previously been shown to regulate CpG methylation at repetitive sequences. We provide evidence that Lsh also controls genome-wide cytosine methylation at nonrepeat sequences and relate those changes to alterations in H4K4me3 modification and gene expression. Deletion of Lsh alters the allocation of cytosine methylation in chromosomal regions of 50 kb to 2 Mb and, in addition, leads to changes in the methylation profile at the 5' end of genes. Furthermore, we demonstrate that loss of Lsh promotes--as well as prevents--cytosine methylation. Our data indicate that Lsh is an epigenetic modulator that is critical for normal distribution of cytosine methylation throughout the murine genome.

Epigenome analyses using BAC microarrays identify evolutionary conservation of tissue-specific methylation of SHANK3.

CpG islands are present in one-half of all human and mouse genes and typically overlap with promoters or exons. We developed a method for high-resolution analysis of the methylation status of CpG islands genome-wide, using arrays of BAC clones and the methylation-sensitive restriction enzyme NotI. Here we demonstrate the accuracy and specificity of the method. By computationally mapping all NotI sites, methylation events can be defined with single-nucleotide precision throughout the genome. We also demonstrate the unique expandability of the array method using a different methylation-sensitive restriction enzyme, BssHII. We identified and validated new CpG island loci that are methylated in a tissue-specific manner in normal human tissues. The methylation status of the CpG islands is associated with gene expression for several genes, including SHANK3, which encodes a structural protein in neuronal postsynaptic densities. Defects in SHANK3 seem to underlie human 22q13 deletion syndrome. Furthermore, these patterns for SHANK3 are conserved in mice and rats.

Immuno-Microbial Signature of Vaccine-Induced Immunity against SARS-CoV-2.

Although vaccines address critical public health needs, inter-individual differences in responses are not always considered in their development. Understanding the underlying basis for these differences is needed to optimize vaccine effectiveness and ultimately improve disease control. In this pilot study, pre- and post-antiviral immunological and gut microbiota features were characterized to examine inter-individual differences in SARS-CoV-2 mRNA vaccine response. Blood and stool samples were collected before administration of the vaccine and at 2-to-4-week intervals after the first dose. A cohort of 14 adults was separated post hoc into two groups based on neutralizing antibody levels (high [HN] or low [LN]) at 10 weeks following vaccination. Bivariate correlation analysis was performed to examine associations between gut microbiota, inflammation, and neutralization capacity at that timepoint. These analyses revealed significant differences in gut microbiome composition and inflammation states pre-vaccination, which predicted later viral neutralization capacity, with certain bacterial taxa, such as those in the genus Prevotella, found at higher abundance in the LN vs HN group that were also negatively correlated with a panel of inflammatory factors such as IL-17, yet positively correlated with plasma levels of the high mobility group box 1 (HMGB-1) protein at pre-vaccination. In particular, we observed a significant inverse relationship (Pearson = -0.54, p = 0.03) between HMGB-1 pre-vaccination and neutralization capacity at 10 weeks post-vaccination. Consistent with known roles as mediators of inflammation, our results altogether implicate HMGB-1 and related gut microbial signatures as potential biomarkers in predicting SARS-CoV-2 mRNA vaccine effectiveness measured by the production of viral neutralization antibodies.

Socioeconomic Status, Lifestyle, and DNA Methylation Age Among Racially and Ethnically Diverse Adults: NIMHD Social Epigenomics Program.

Importance: Variation in DNA methylation at specific loci estimates biological age, which is associated with morbidity, mortality, and social experiences. Aging estimates known as epigenetic clocks, including the Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE), were trained on data predominately from individuals of European ancestry; however, limited research has explored DunedinPACE in underrepresented populations experiencing health disparities. Objective: To investigate associations of neighborhood and individual sociobehavioral factors with biological aging in a racially and ethnically diverse population. Design, Setting, and Participants: This cohort study, part of the Multiethnic Cohort study conducted from May 1993 to September 1996 to examine racial and ethnic disparities in chronic diseases, integrated biospecimen and self-reported data collected between April 2004 and November 2005 from healthy Hawaii residents aged 45 to 76 years. These participants self-identified as of Japanese American, Native Hawaiian, or White racial and ethnic background. Data were analyzed from January 2022 to May 2024. Main Outcomes and Measures: DNA methylation data were generated from monocytes enriched from cryopreserved lymphocytes and used to derive DunedinPACE scores from November 2017 to June 2021. Neighborhood social economic status (NSES) was estimated from 1990 US Census Bureau data to include factors such as educational level, occupation, and income. Individual-level factors analyzed included educational level, body mass index (BMI), physical activity (PA), and diet quality measured by the Healthy Eating Index (HEI). Linear regression analysis of DunedinPACE scores was used to examine their associations with NSES and sociobehavioral variables. Results: A total of 376 participants were included (113 [30.1%] Japanese American, 144 [38.3%] Native Hawaiian, and 119 [31.6%] White; 189 [50.3%] were female). Mean (SE) age was 57.81 (0.38) years. Overall, mean (SE) DunedinPACE scores were significantly higher among females than among males (1.28 [0.01] vs 1.25 [0.01]; P = .005); correlated negatively with NSES (R = -0.09; P = .08), HEI (R = -0.11; P = .03), and educational attainment (R = -0.15; P = .003) and positively with BMI (R = 0.31; P < .001); and varied by race and ethnicity. Native Hawaiian participants exhibited a higher mean (SE) DunedinPACE score (1.31 [0.01]) compared with Japanese American (1.25 [0.01]; P < .001) or White (1.22 [0.01]; P < .001) participants. Controlling for age, sex, HEI, BMI, and NSES, linear regression analyses revealed a negative association between educational level and DunedinPACE score among Japanese American (ß, -0.005 [95% CI, -0.013 to 0.002]; P = .03) and Native Hawaiian (ß, -0.003 [95% CI, -0.011 to 0.005]; P = .08) participants, yet this association was positive among White participants (ß, 0.007; 95% CI, -0.001 to 0.015; P = .09). Moderate to vigorous PA was associated with lower DunedinPACE scores only among Native Hawaiian participants (ß, -0.006; 95% CI, -0.011 to -0.001; P = .005), independent of NSES. Conclusions and Relevance: In this study of a racially and ethnically diverse sample of 376 adults, low NSES was associated with a higher rate of biological aging measured by DunedinPACE score, yet individual-level factors such as educational level and physical activity affected this association, which varied by race and ethnicity. These findings support sociobehavioral interventions in addressing health inequities.

HMGB1 mediates microbiome-immune axis dysregulation underlying reduced neutralization capacity in obesity-related post-acute sequelae of SARS-CoV-2.

While obesity is a risk factor for post-acute sequelae of SARS-CoV-2 infection (PASC, "long-COVID"), the mechanism(s) underlying this phenomenon remains poorly understood. To address this gap in knowledge, we performed a 6-week longitudinal study to examine immune activity and gut microbiome dysbiosis in post-acute stage patients recovering from SARS-CoV-2 infection. Self-reported symptom frequencies and blood samples were collected weekly, with plasma assessed by ELISA and Luminex for multiple biomarkers and immune cell profiling. DNA from stool samples were collected at the early stage of recovery for baseline assessments of gut microbial composition and diversity using 16S-based metagenomic sequencing. Multiple regression analyses revealed obesity-related PASC linked to a sustained proinflammatory immune profile and reduced adaptive immunity, corresponding with reduced gut microbial diversity. In particular, enhanced signaling of the high mobility group box 1 (HMGB1) protein was found to associate with this dysregulation, with its upregulated levels in plasma associated with significantly impaired viral neutralization that was exacerbated with obesity. These findings implicate HMGB1 as a candidate biomarker of PASC, with potential applications for risk assessment and targeted therapies.

Ketogenic Diet Induced Shifts in the Gut Microbiome Associate with Changes to Inflammatory Cytokines and Brain-Related miRNAs in Children with Autism Spectrum Disorder.

In this interventional pilot study, we investigated the effects of a modified ketogenic diet (KD) on children with autism spectrum disorder (ASD). We previously observed improved behavioral symptoms in this cohort following the KD; this trial was registered with Clinicaltrials.gov (NCT02477904). This report details the alterations observed in the microbiota, inflammation markers, and microRNAs of seven children following a KD for a duration of 4 months. Our analysis included blood and stool samples, collected before and after the KD. After 4 months follow up, we found that the KD led to decreased plasma levels of proinflammatory cytokines (IL-12p70 and IL-1b) and brain-derived neurotrophic factor (BDNF). Additionally, we observed changes in the gut microbiome, increased expression of butyrate kinase in the gut, and altered levels of BDNF-associated miRNAs in the plasma. These cohort findings suggest that the KD may positively influence ASD sociability, as previously observed, by reducing inflammation, reversing gut microbial dysbiosis, and impacting the BDNF pathway related to brain activity.

Avirulent UG10 Entamoeba histolytica mutant derived from HM-1:IMSS strain shows limited genome variability and aberrant 5-methyl cytosine genomic distribution.

Entamoeba histolytica, an intestinal parasite of global significance, poses substantial health risks with its associated high morbidity and mortality rates. Despite the current repertoire of molecular tools for the study of gene function in, the regulatory mechanisms governing its pathogenicity remain largely unexplored. This knowledge gap underscores the need to elucidate key genetic determinants orchestrating cellular functions critical to its virulence. Previously, our group generated an avirulent strain, termed UG10, with the same genetic background as the HM1:IMSS strain. UG10 strain, despite showing normal expression levels of well-known virulence factors, was unable to perform in-vitro and in-vivo activities related to amoebic virulence. In this study, we aimed to uncover the genome-wide modifications that rendered the avirulent phenotype of the UG10 strain through whole-genome sequencing. As a complementary approach, we conducted Methylated DNA Immunoprecipitation coupled with sequencing (MeDIP-seq) analysis on both the highly virulent HM1:IMSS strain and the low-virulence UG10 strain to uncover the genome-wide methylation profile. These dual methodologies revealed two aspects of the UG10 avirulent strain. One is the random integration of fragments from the ribosomal gene cluster and tRNA genes, ranging from 120 to 400 bp; and secondly, a clear, enriched methylation profile in the coding and non-coding strand relative to the start codon sequence in genes encoding small GTPases, which is associated with the previously described avirulent phenotype. This study provides the foundation to explore other genetic and epigenetic regulatory circuitries in E. histolytica and novel targets to understand the pathogenic mechanism of this parasite.

Sequencing the SARS-CoV-2 Genome from Stool Samples of Post-acute Cases Implicates a Novel Mutation Associated with Reduced Antibody Neutralization.

Whole-genome SARS-CoV-2 sequencing tools are crucial for tracking the COVID-19 pandemic. However, current techniques require sampling of actively infectious patients following COVID-19 testing to recover enough SARS-CoV-2 RNA from the nasopharyngeal passage, which rapidly clears during the first few weeks of infection. A prospective assessment of the viral genome sourced from recovered non-infectious patients would greatly facilitate epidemiological tracking. Thus, we developed a protocol to isolate and sequence the genome of SARS-CoV-2 from stool samples of post-acute SARS-CoV-2 patients, at timepoints ranging from 10-120 days after onset of symptoms. Stool samples were collected from patients at varying timepoints post-convalescence, and viral DNA was isolated and sequenced using the QIAamp Viral RNA Mini Kit (Qiagen Inc.) and Ion Ampliseq™ Library Kit Plus (Life Technologies Corporation). Capacity of neutralizing antibodies in patient plasma was tested using a Luminex panel (Coronavirus Ig Total Human 11-Plex ProcartaPlex™ Panel, ThermoFisher). Of 64 samples obtained from post-acute patients, 21 (32.8%) yielded sufficient material for whole-genome sequencing. This allowed us to identify widely divergent phylogenetic relativity of the SARS-CoV-2 genome from post-acute patients living in the same households and infected around the same time. Additionally, we observed that individuals who recovered from infection expressed varying degrees of antibodies against SARS-CoV-2 structural proteins that corresponded to distinct variants. Interestingly, we identified a novel point mutation in the viral genome where infected patients expressed antibodies with a significantly reduced capacity to neutralize the virus in vitro relative to that of those infected with the wild-type strain. Altogether, we demonstrate a protocol to successfully sequence the SARS-CoV-2 genome from stool samples from patients up to 4 months post-infection, which can be applied to studies that assess the relationship between variants and immune response post-hoc and safe monitoring of the SARS-CoV-2 genome during the pandemic.

Examining the immunoepigenetic-gut microbiome axis in the context of self-esteem among Native Hawaiians and other Pacific Islanders.

Introduction: Native Hawaiian and other Pacific Islander (NHPI) populations experience higher rates of immunometabolic diseases compared to other racial-ethnic groups in Hawaii. As annual NHPI mortality rates for suicide and type 2 diabetes mellitus (T2DM) exceed those of the state as a whole, understanding the social and biological mechanisms underlying these disparities are urgently needed to enable preventive strategies. Methods: A community-based approach was used to investigate the immunoepigenetic-gut microbiome axis in an NHPI-enriched cohort of Oahu residents (N = 68). Self-esteem (SE) data was collected using a modified Rosenberg self-esteem (SE) assessment as a proxy measure for mental wellbeing in consideration for cultural competency. T2DM status was evaluated using point-of-care A1c (%) tests. Stool samples were collected for 16s-based metagenomic sequencing analyses. Plasma from blood samples were isolated by density-gradient centrifugation. Peripheral blood mononuclear cells (PBMCs) were collected from the same samples and enriched for monocytes using negative selection techniques. Flow-cytometry was used for immunoprofiling assays. Monocyte DNA was extracted for Illumina EPIC array-based methylation analysis. Results: Compared to individuals with normal SE (NSE), those with low SE (LSE) exhibited significantly higher plasma concentrations (pg/ml) of proinflammatory cytokines IL-8 (p = 0.051) and TNF-α (p = 0.011). Metagenomic analysis revealed that the relative abundance (%) of specific gut bacteria significantly differed between SE groups - some of which directly correlated with SE scores. Gene ontology analysis revealed that 104 significantly differentially methylated loci (DML) between SE groups were preferentially located at genes involved in immunometabolic processes. Horvath clock analyses indicated epigenetic age (Epi-Age) deceleration in individuals with LSE and acceleration in individuals with NSE (p = 0.042), yet was not reproduced by other clocks. Discussion: These data reveal novel differences in the immunoepigenetic-gut microbiome axis with respect to SE, warranting further investigation into its relationship to brain activity and mental health in NHPI. Unexpected results from Epi-Age analyses warrant further investigation into the relationship between biological age and disparate health outcomes among the NHPI population. The modifiable component of epigenetic processes and the gut microbiome makes this axis an attractive target for potential therapeutics, biomarker discovery, and novel prevention strategies.

Epigenome mapping in normal and disease States.

Epigenomes are comprised, in part, of all genome-wide chromatin modifications, including DNA methylation and histone modifications. Unlike the genome, epigenomes are dynamic during development and differentiation to establish and maintain cell type-specific gene expression states that underlie cellular identity and function. Chromatin modifications are particularly labile, providing a mechanism for organisms to respond and adapt to environmental cues. Results from studies in animal models clearly demonstrate that epigenomic variability leads to phenotypic variability, including susceptibility to disease that is not recognized at the DNA sequence level. Thus, capturing epigenomic information is invaluable for comprehensively understanding development, differentiation, and disease. Herein, we provide a brief overview of epigenetic processes, how they are relevant to human health, and review studies using technologies that enable epigenome mapping. We conclude by describing feasible applications of epigenome mapping, focusing on epigenome-wide association studies (eGWAS), which have the potential to revolutionize current studies of human diseases and will likely promote the discovery of novel diagnostic, preventative, and treatment strategies.

The Effects of COVID-19 Vaccine Mandates in Hawaii.

Having been affected by the highest increase in COVID-19 cases since the start of the pandemic, Honolulu and Maui counties in Hawaii implemented vaccine passport mandates for select industries in September 2021. However, the degree to which such mandates impacted COVID-19 mitigation efforts and economics remains poorly understood. Herein, we describe the effects of these mandates on changes in three areas using difference-in-difference regression models: (1) business foot traffic; (2) number of COVID-19 cases per 100,000 individuals, and (3) COVID-19 vaccination rates across counties affected or unaffected by the mandates. We observed that although businesses affected by mandates experienced a 6.7% decrease in foot traffic over the 14 weeks after the mandates were implemented, the number of COVID-19 cases decreased by 19.0%. Notably, the vaccination rate increased by 1.41% in counties that implemented mandates. In addition, towards the end of the studied period, the level of foot traffic at impacted businesses converged towards the level of that of non-impacted businesses. As such, the trade-off in temporary losses at businesses was met with significant gains in public health and safety.