Epigenome-Wide Meta-Analysis Reveals Differential DNA Methylation Associated With Estimated Glomerular Filtration Rate Among African American Men With HIV.

Introduction: People with HIV (PWH) of African ancestry have faster decline of kidney function and faster progression to end-stage renal disease than PWH of European ancestry. DNA methylation have been associated with kidney function in the general population, however, their relationships are unclear for PWH of African ancestry. Methods: We performed epigenome-wide association studies (EWAS) of estimated glomerular filtration rate (eGFR) among PWH of African ancestry in 2 subsets of the Veterans Aging Cohort Study cohort (N = 885), followed by a meta-analysis to combine the results. Replication was conducted among independent African American samples without HIV. Results: DNA methylation sites cg17944885 near Zinc Finger Family Member 788 (ZNF788) and Zinc Finger Protein 20 (ZNF20), and cg06930757 in SHANK1 were significantly associated with eGFR among PWH of African ancestry (false discovery rate < 0.05). DNA methylation site cg17944885 was also associated with eGFR among different populations including African Americans without HIV. Conclusions: Our study attempted to address an important gap in the literature and to understand the role of DNA methylation in renal diseases in PWH of African ancestry. Replication of cg17944885 among different populations suggests there may be a common pathway for renal diseases progression among PWH and people without HIV, and across different ancestral groups. Our results suggest that genes ZNF788/ZNF20 and SHANK1 could be involved in a pathway linking DNA methylation to renal diseases among PWH and are worth further investigation.

COVID-19-Related manuscripts: lag from preprint to publication.

OBJECTIVE: Preprints have had a prominent role in the swift scientific response to COVID-19. Two years into the pandemic, we investigated how much preprints had contributed to timely data sharing by analyzing the lag time from preprint posting to journal publication. RESULTS: To estimate the median number of days between the date a manuscript was posted as a preprint and the date of its publication in a scientific journal, we analyzed preprints posted from January 1, 2020, to December 31, 2021 in the NIH iSearch COVID-19 Portfolio database and performed a Kaplan-Meier (KM) survival analysis using a non-mixture parametric cure model. Of the 39,243 preprints in our analysis, 7712 (20%) were published in a journal, after a median lag of 178 days (95% CI: 175-181). Most of the published preprints were posted on the bioRxiv (29%) or medRxiv (65%) servers, which allow authors to choose a subject category when posting. Of the 20,698 preprints posted on these two servers, 7358 (36%) were published, including approximately half of those categorized as biochemistry, biophysics, and genomics, which became published articles within the study interval, compared with 29% categorized as epidemiology and 26% as bioinformatics.

Epigenome-wide association study of biomarkers of liver function identifies albumin-associated DNA methylation sites among male veterans with HIV.

Background: Liver disease (LD) is an important cause of morbidity and mortality for people with HIV (PWH). The molecular factors linked with LD in PWH are varied and incompletely characterized. We performed an epigenome-wide association study (EWAS) to identify associations between DNA methylation (DNAm) and biomarkers of liver function-aspartate transaminase, alanine transaminase, albumin, total bilirubin, platelet count, FIB-4 score, and APRI score-in male United States veterans with HIV. Methods: Blood samples and clinical data were obtained from 960 HIV-infected male PWH from the Veterans Aging Cohort Study. DNAm was assessed using the Illumina 450K or the EPIC 850K array in two mutually exclusive subsets. We performed a meta-analysis for each DNAm site measured by either platform. We also examined the associations between four measures of DNAm age acceleration (AA) and liver biomarkers. Results: Nine DNAm sites were positively associated with serum albumin in the meta-analysis of the EPIC and 450K EWAS after correcting for multiple testing. Four DNAm sites (cg16936953, cg18942579, cg01409343, and cg12054453), annotated within the TMEM49 and four of the remaining five sites (cg18181703, cg03546163, cg20995564, and cg23966214) annotated to SOCS3, FKBP5, ZEB2, and SAMD14 genes, respectively. The DNAm site, cg12992827, was not annotated to any known coding sequence. No significant associations were detected for the other six liver biomarkers. Higher PhenoAA was significantly associated with lower level of serum albumin (ß = -0.007, p-value = 8.6 × 10-4, CI: -0.011116, -0.002884). Conclusion: We identified epigenetic associations of both individual DNAm sites and DNAm AA with liver function through serum albumin in men with HIV. Further replication analyses in independent cohorts are warranted to confirm the epigenetic mechanisms underlying liver function and LD in PWH.

COVID-19 GPH: tracking the contribution of genomics and precision health to the COVID-19 pandemic response.

The scientific response to the COVID-19 pandemic has produced an abundance of publications, including peer-reviewed articles and preprints, across a wide array of disciplines, from microbiology to medicine and social sciences. Genomics and precision health (GPH) technologies have had a particularly prominent role in medical and public health investigations and response; however, these domains are not simply defined and it is difficult to search for relevant information using traditional strategies. To quantify and track the ongoing contributions of GPH to the COVID-19 response, the Office of Genomics and Precision Public Health at the Centers for Disease Control and Prevention created the COVID-19 Genomics and Precision Health database (COVID-19 GPH), an open access knowledge management system and publications database that is continuously updated through machine learning and manual curation. As of February 11, 2022, COVID-GPH contained 31,597 articles, mostly on pathogen and human genomics (72%). The database also includes articles describing applications of machine learning and artificial intelligence to the investigation and control of COVID-19 (28%). COVID-GPH represents about 10% (22983/221241) of the literature on COVID-19 on PubMed. This unique knowledge management database makes it easier to explore, describe, and track how the pandemic response is accelerating the applications of genomics and precision health technologies. COVID-19 GPH can be freely accessed via https://phgkb.cdc.gov/PHGKB/coVInfoStartPage.action .

Interaction between genetics and smoking in determining risk of coronary artery diseases.

Coronary artery disease (CAD) is a preeminent cause of death, and smoking is a strong risk factor for CAD. Genetic factors contribute to the development of CAD, but the interplay between genetic predisposition and smoking history in CAD remains unclear. Using data from the UK Biobank, we constructed several genetic risk scores (GRSs) based on known CAD loci and assessed their interactions with smoking for the development of incident CAD in 307,147 participants of European ancestry who were free of CAD. We fitted Cox proportional hazard models and assessed gene-smoking interaction on both multiplicative and additive scales. Overall, we found no multiplicative interactions, but observed a synergistic additive interaction of GRS with both smoking status and pack-years of smoking, finding that the absolute CAD risk due to smoking was higher for those with high genetic risk. Trait-based sub-GRSs suggested smoking status and smoking intensity measured by pack-years might confer gene-smoking interaction effects with different intermediate risk factors for CAD. Our study results suggest that genetics could modify the effects of smoking on CAD and highlight the value of addressing gene-lifestyle interactions on both additive and multiplicative scales.

Epigenome-wide epidemiologic studies of human immunodeficiency virus infection, treatment, and disease progression.

Despite significant advances in the treatment and care of people with HIV (PWH), several challenges remain in our understanding of disease pathogenesis to improve patient care. HIV infection can modify the host epigenome and as such can impact disease progression, as well as the molecular processes driving non-AIDS comorbidities in PWH. Epigenetic epidemiologic studies including epigenome-wide association studies (EWAS) offer a unique set of tools to expand our understanding of HIV disease and to identify novel strategies applicable to treatment and diagnosis in this patient population. In this review, we summarize the current state of knowledge from epigenetic epidemiologic studies of PWH, identify the main challenges of this approach, and highlight future directions for the field. Emerging epigenetic epidemiologic studies of PWH can expand our understanding of HIV infection and health outcomes, improve scientific validity through collaboration and replication, and increase the coverage of diverse populations affected by the global HIV pandemic. Through this review, we hope to highlight the potential of EWAS as a tool for HIV research and to engage more investigators to explore its application to important research questions.

DNA Methylation of TXNIP Independently Associated with Inflammation and Diabetes Mellitus in Twins.

Thioredoxin-interacting protein (TXNIP) plays a key role in diabetes development and prognosis through its role in pancreatic ß-cell dysfunction and death as well as in upregulating the inflammatory response in hyperglycemia. DNA methylation (DNAm) of TXNIP (TXNIP-cg19693031) is associated with the prevalence and incidence of type 2 diabetes (T2D); however, its role in inflammation and its relationship with T2D remain unclear. We aimed to investigate the epigenetic associations of TXNIP-cg19693031 with a panel of inflammatory biomarkers and to examine whether these inflammatory biomarkers modify the association between TXNIP-cg19693031 methylation and diabetes in 218 middle-aged male twins from the Emory Twin Study. We confirmed the association of TXNIP-cg19693031 DNAm with T2D, as well as with HbA1c, insulin and fasting glucose. We found that hypomethylation at TXNIP-cg19693031 is strongly associated with both type 2 diabetes and higher levels of inflammatory biomarkers (VCAM-1, ICAM-1, MMP-2, sRAGE and P-selectin); however, the relationship between TXNIP-cg19693031 and T2D is independent of the levels of these inflammatory biomarkers. Our results suggest that DNA methylation of TXNIP is linked with multiple biological processes, through which the TXNIP may have broad influence on chronic disease risk.

Sexual Differences in Genetic Predisposition of Coronary Artery Disease.

BACKGROUND: The genomic structure that contributes to the risk of coronary artery disease (CAD) can be evaluated as a risk score of multiple variants. However, sex differences have not been fully examined in applications of genetic risk score (GRS) of CAD. METHODS: Using data from the UK Biobank, we constructed a CAD-GRS based on all known loci, 3 mediating trait-based (blood pressure, lipids, and body mass index) subscores, and a genome-wide polygenic risk score based on 1.1 million variants. The differences in genetic associations with prevalent and incident CAD between men and women were investigated among 317 509 unrelated individuals of the European ancestry. We also assessed interactions with sex for 161 individual loci included in the comprehensive GRS. RESULTS: For both prevalent and incident CAD, the associations of comprehensive and genome-wide GRSs were stronger among men than women. Using a score of 161 loci, we observed a 2.4× higher risk for incident CAD comparing men with high genetic risk to men with low genetic risk but an 80% greater risk comparing women with high genetic risk to women with low genetic risk (interaction P=0.002). Of the 3 subscores, the blood pressure-associated subscore exhibited sex differences (interaction P=0.0004 per SD increase in subscore). Analysis of individual variants identified a novel gene-sex interaction at locus 21q22.11. CONCLUSIONS: Sexual differences in genetic predisposition should be considered in future studies of CAD, and GRSs should not be assumed to perform equally well in men and women.

Evaluation of the Host Genetic Effects of Tuberculosis-Associated Variants Among Patients With Type 1 and Type 2 Diabetes Mellitus.

BACKGROUND: Understanding the link between tuberculosis (TB) and diabetes is increasingly important as public health responds to the growing global burden of noncommunicable diseases. Genetic association studies have identified numerous host genetic variants linked to TB; however, potential host genetic mechanisms linking TB and diabetes remain unexplored. METHODS: We used genetic and phenotypic data from the UK Biobank to evaluate the association of 6 previously reported TB-related host genetic variants (genome-wide significant associations from published studies) with diabetes. The study included 409 692 adults of European ancestry including 2177 with type 1 diabetes mellitus (T1DM) and 13 976 with type 2 diabetes mellitus (T2DM), defined by ICD-10 diagnosis codes. RESULTS: Of the 6 TB-associated single nucleotide polymorphisms (SNPs), 2 were associated with T1DM and 3 with T2DM, after adjusting for age, sex, body mass index, smoking, alcohol use, and population structure. After correction for multiple testing, SNPs rs2894257 and rs3135359 (HLA-DRA-DQA1) were associated with T1DM (rs2894257: odds ratio [OR], 1.32; 95% confidence interval [CI], 1.21-1.45; rs3135359: OR, 1.72; 95% CI, 1.57-1.88) and T2DM (rs2894257: OR, 1.11; 95% CI, 1.08-1.15; rs3135359: OR, 1.06; 95% CI, 1.025-1.096). The associations with T2DM weakened for rs2894257 and rs3135359 after further exclusion of probable T1DM cases defined by International Statistical Classification of Diseases and Related Health Problems (ICD-10) codes. SNP rs4733781 on chromosome 8 (ASAP1 gene) was associated with T2DM after exclusion of T1DM cases. CONCLUSIONS: Our findings suggest that common host genetic effects may play a role in the molecular mechanism linking TB and diabetes. Future large genetic studies of TB and diabetes should focus on developing countries with high burdens of infectious and chronic diseases.

Novel citation-based search method for scientific literature: a validation study.

BACKGROUND: We recently developed CoCites, a citation-based search method that is designed to be more efficient than traditional keyword-based methods. The method begins with identification of one or more highly relevant publications (query articles) and consists of two searches: the co-citation search, which ranks publications on their co-citation frequency with the query articles, and the citation search, which ranks publications on frequency of all citations that cite or are cited by the query articles. METHODS: We aimed to reproduce the literature searches of published systematic reviews and meta-analyses and assess whether CoCites retrieves all eligible articles while screening fewer titles. RESULTS: A total of 250 reviews were included. CoCites retrieved a median of 75% of the articles that were included in the original reviews. The percentage of retrieved articles was higher (88%) when the query articles were cited more frequently and when they had more overlap in their citations. Applying CoCites to only the highest-cited article yielded similar results. The co-citation and citation searches combined were more efficient when the review authors had screened more than 500 titles, but not when they had screened less. CONCLUSIONS: CoCites is an efficient and accurate method for finding relevant related articles. The method uses the expert knowledge of authors to rank related articles, does not depend on keyword selection and requires no special expertise to build search queries. The method is transparent and reproducible.

Epigenetic Associations With Estimated Glomerular Filtration Rate Among Men With Human Immunodeficiency Virus Infection.

BACKGROUND: People living with human immunodeficiency virus (HIV) infection have higher risk for chronic kidney disease (CKD), defined by a reduced estimated glomerular filtration rate (eGFR). Previous studies have implicated epigenetic changes related to CKD; however, the mechanism of HIV-related CKD has not been thoroughly investigated. METHODS: We conducted an epigenome-wide association study of eGFR among 567 HIV-positive and 117 HIV-negative male participants in the Veterans Aging Cohort Study to identify epigenetic signatures of kidney function. RESULTS: By surveying more than 400 000 cytosine guanine dinucleotide (CpG) sites measured from peripheral blood mononuclear cells, we identified 15 sites that were significantly associated with eGFR (false discovery rate Q value < 0.05) among HIV-positive participants. The most significant CpG sites, located at MAD1L1, TSNARE1/BAI1, and LTV1, were all negatively associated with eGFR (cg06329547, P = 5.25 × 10-9; cg23281907, P = 1.37 × 10-8; cg18368637, P = 5.17 × 10-8). We also replicated previously reported eGFR-associated CpG sites including cg17944885 (P = 2.5 × 10-5) located between ZNF788 and ZNF20 on chromosome 19 in the pooled population. CONCLUSIONS: In this study we uncovered novel epigenetic associations with kidney function among people living with HIV and suggest potential epigenetic mechanisms linked with HIV-related CKD risk.

Pathogen Genomics in Public Health.

Rapid advances in DNA sequencing technology ("next-generation sequencing") have inspired optimism about the potential of human genomics for "precision medicine." Meanwhile, pathogen genomics is already delivering "precision public health" through more effective investigations of outbreaks of foodborne illnesses, better-targeted tuberculosis control, and more timely and granular influenza surveillance to inform the selection of vaccine strains. In this article, we describe how public health agencies have been adopting pathogen genomics to improve their effectiveness in almost all domains of infectious disease. This momentum is likely to continue, given the ongoing development in sequencing and sequencing-related technologies.

DNA Methylation Markers of Type 2 Diabetes Mellitus Among Male Veterans With or Without Human Immunodeficiency Virus Infection.

Epigenetic modifications such as DNA methylation are associated with both human immunodeficiency virus (HIV) infection and type 2 diabetes mellitus (T2DM). We investigated epigenetic associations with T2DM according to HIV infection status and assessed interaction effects among 681 male participants of the Veterans Aging Cohort Study. Methylation at previously reported sites, cg1963031 (TXNIP), cg18181703 (SOCS3), and cg09152259 (PROC), was significantly associated with T2DM in HIV-infected individuals. We identified 3 novel associations with suggestive statistical significance: cg1231141 (ADAMTS2), cg19534769 (HGFAC), and cg13163919 (TLE3). Suggestive interaction with HIV infection status was found at cg17862404 (TSC22D1). The implicated genes are involved in inflammation, pancreatic ß-cell function, and T2DM pathogenesis.

From public health genomics to precision public health: a 20-year journey.

In this paper, we review the evolution of the field of public health genomics in the United States in the past two decades. Public health genomics focuses on effective and responsible translation of genomic science into population health benefits. We discuss the relationship of the field to the core public health functions and essential services, review its evidentiary foundation, and provide examples of current US public health priorities and applications. We cite examples of publications to illustrate how Genetics in Medicine reflected the evolution of the field. We also reflect on how public-health genomics is contributing to the emergence of "precision public health" with near-term opportunities offered by the US Precision Medicine (AllofUs) Initiative.

Integrating Advanced Molecular Technologies into Public Health.

Advances in laboratory and information technologies are transforming public health microbiology. High-throughput genome sequencing and bioinformatics are enhancing our ability to investigate and control outbreaks, detect emerging infectious diseases, develop vaccines, and combat antimicrobial resistance, all with increased accuracy, timeliness, and efficiency. The Advanced Molecular Detection (AMD) initiative has allowed the Centers for Disease Control and Prevention (CDC) to provide leadership and coordination in integrating new technologies into routine practice throughout the U.S. public health laboratory system. Collaboration and partnerships are the key to navigating this transition and to leveraging the next generation of methods and tools most effectively for public health.

A knowledge base for tracking the impact of genomics on population health.

PURPOSE: We created an online knowledge base (the Public Health Genomics Knowledge Base (PHGKB)) to provide systematically curated and updated information that bridges population-based research on genomics with clinical and public health applications. METHODS: Weekly horizon scanning of a wide variety of online resources is used to retrieve relevant scientific publications, guidelines, and commentaries. After curation by domain experts, links are deposited into Web-based databases. RESULTS: PHGKB currently consists of nine component databases. Users can search the entire knowledge base or search one or more component databases directly and choose options for customizing the display of their search results. CONCLUSION: PHGKB offers researchers, policy makers, practitioners, and the general public a way to find information they need to understand the complicated landscape of genomics and population health.Genet Med 18 12, 1312-1314.