Publications by authors named "Lifang Hou"

287 Publications

Glioblastoma as an age-related neurological disorder in adults.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab125. Epub 2021 Sep 4.

Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Background: Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDH GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDH GBM have a median age of diagnosis at 68-70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM.

Methods: The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship.

Results: Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve.

Conclusions: Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDH GBM patient outcomes.
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http://dx.doi.org/10.1093/noajnl/vdab125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500689PMC
September 2021

Cisplatin, environmental metals, and cardiovascular disease: an urgent need to understand underlying mechanisms.

Cardiooncology 2021 Oct 10;7(1):34. Epub 2021 Oct 10.

Division of Hematology-Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

Significantly increased risks of cardiovascular disease occur in testicular cancer survivors given cisplatin-based chemotherapy. The postulated mechanism of platinum-based chemotherapy's vascular toxicity has been thought secondary to its different early- and late- effects on vascular injury, endothelial dysfunction, and induction of a hypercoagulable state. We highlight for the first time the similarities between platinum-associated vascular adverse events and the vascular toxicity associated with other xenobiotic-metal contaminants. The vascular toxicity seen in large epidemiologic studies of testicular cancer survivors may in part be similar and mechanistically linked to the risk seen in environmental heavy metal contaminants linked to cardiovascular disease. Future research should be directed to better understand the magnitude of the adverse cardiovascular effects of platinum and to elucidate the underlying mechanisms of action.
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http://dx.doi.org/10.1186/s40959-021-00120-zDOI Listing
October 2021

Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.

Am J Hum Genet 2021 Oct 27;108(10):1836-1851. Epub 2021 Sep 27.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.
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http://dx.doi.org/10.1016/j.ajhg.2021.08.007DOI Listing
October 2021

Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative.

Hum Mol Genet 2021 Sep 6. Epub 2021 Sep 6.

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.
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http://dx.doi.org/10.1093/hmg/ddab252DOI Listing
September 2021

Impact of paternal education on epigenetic ageing in adolescence and mid-adulthood: a multi-cohort study in the USA and Mexico.

Int J Epidemiol 2021 Sep 17. Epub 2021 Sep 17.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Both parental and neighbourhood socio-economic status (SES) are linked to poorer health independently of personal SES measures, but the biological mechanisms are unclear. Our objective was to examine these influences via epigenetic age acceleration (EAA)-the discrepancy between chronological and epigenetic ages.

Methods: We examined three USA-based [Coronary Artery Risk Disease in Adults (CARDIA) study, Fragile Families and Child Wellbeing Study (FFCWS) and Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS)] and one Mexico-based (Project Viva) cohort. DNA methylation was measured using Illumina arrays, personal/parental SES by questionnaire and neighbourhood disadvantage from geocoded address. In CARDIA, we examined the most strongly associated personal, parental and neighbourhood SES measures with EAA (Hannum's method) at study years 15 and 20 separately and combined using a generalized estimating equation (GEE) and compared with other EAA measures (Horvath's EAA, PhenoAge and GrimAge calculators, and DunedinPoAm).

Results: EAA was associated with paternal education in CARDIA [GEEs: βsome college = -1.01 years (-1.91, -0.11) and β
Conclusions: These findings suggest that EAA captures epigenetic impacts of paternal education independently of personal SES later in life. Longitudinal studies should explore these associations at different life stages and link them to health outcomes. EAA could be a useful biomarker of SES-associated health and provide important insight into the pathogenesis and prevention of chronic disease.
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http://dx.doi.org/10.1093/ije/dyab196DOI Listing
September 2021

Epigenetic Age Acceleration Reflects Long-Term Cardiovascular Health.

Circ Res 2021 Oct 25;129(8):770-781. Epub 2021 Aug 25.

Department of Preventive Medicine (B.T.J., T.G., Y.Z., D.N., N.B.A., A.K., H.N., K.L., P.G., L.H., D.L.-J.), Feinberg School of Medicine, Northwestern University, Chicago, IL.

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.121.318965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484046PMC
October 2021

Epigenome-wide association study of mitochondrial genome copy number.

Hum Mol Genet 2021 Aug 20. Epub 2021 Aug 20.

Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

We conducted cohort- and race-specific epigenome-wide association analyses of mtDNA copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age 57-67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated CpG sites (p < 1 x 10-7), with a 0.7 to 3.0 standard deviation increase (3 CpGs) or decrease (18 CpGs) in mtDNA CN corresponding to a 1% increase in DNA methylation. Several significant CpGs have been reported to be associated with at least two risk factors (e.g. chronological age or smoking) for cardiovascular disease (CVD). Five genes (PRDM16, NR1H3, XRCC3, POLK, and PDSS2), which harbor nine significant CpGs, are known to be involved in mitochondrial biosynthesis and functions. For example, NR1H3 encodes a transcription factor that is differentially expressed during an adipose tissue transition. The methylation level of cg09548275 in NR1H3 was negatively associated with mtDNA CN (effect size = -1.71, p = 4 x 10-8) and positively associated with the NR1H3 expression level (effect size = 0.43, p = 0.0003), which indicates that the methylation level in NR1H3 may underlie the relationship between mtDNA CN, the NR1H3 transcription factor, and energy expenditure. In summary, the study results suggest that mtDNA CN variation in whole blood is associated with DNA methylation levels in genes that are involved in a wide range of mitochondrial activities. These findings will help reveal molecular mechanisms between mtDNA CN and CVD.
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http://dx.doi.org/10.1093/hmg/ddab240DOI Listing
August 2021

Mediation analysis for survival data with High-Dimensional mediators.

Bioinformatics 2021 Aug 3. Epub 2021 Aug 3.

Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, 63110, USA.

Motivation: Mediation analysis has become a prevalent method to identify causal pathway(s) between an independent variable and a dependent variable through intermediate variable(s). However, little work has been done when the intermediate variables (mediators) are high-dimensional and the outcome is a survival endpoint. In this paper, we introduce a novel method to identify potential mediators in a causal framework of high-dimensional Cox regression.

Results: We first reduce the data dimension through a mediation-based sure independence screening (SIS) method. A de-biased Lasso inference procedure is used for Cox's regression parameters. We adopt a multiple-testing procedure to accurately control the false discovery rate (FDR) when testing high-dimensional mediation hypotheses. Simulation studies are conducted to demonstrate the performance of our method. We apply this approach to explore the mediation mechanisms of 379,330 DNA methylation markers between smoking and overall survival among lung cancer patients in the TCGA lung cancer cohort. Two methylation sites (cg08108679 and cg26478297) are identified as potential mediating epigenetic markers.

Availability: Our proposed method is available with the R package HIMA at https://cran.r-project.org/web/packages/HIMA/.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab564DOI Listing
August 2021

Novel epigenetic link between gestational diabetes mellitus and macrosomia.

Epigenomics 2021 Aug 2;13(15):1221-1230. Epub 2021 Aug 2.

Center for Global Oncology, Institute for Global Health, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Examine maternal gestational diabetes mellitus (GDM), macrosomia and DNA methylation in candidate genes , , , , , ,  and . A total of 1145 children (572 GDM cases and 573 controls) from the Tianjin GDM study, including 177 with macrosomia, had blood DNA collection at median age 5.9 (range: 3.1-10.0). We used logistic regression to screen for associations with GDM and model macrosomia on 37 CpGs, and performed mediation analysis. One CpG was associated with macrosomia at false discovery rate (FDR) <0.05 (cg14428359 in ); two (cg19466922 in and cg26263166 in ) were associated at p < 0.05 but mediated 26 and 13%, respectively. and were previously identified for potential involvement in fetal growth and development (Trial Registration number: NCT01554358 [ClinicalTrials.gov]).
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http://dx.doi.org/10.2217/epi-2021-0096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371577PMC
August 2021

Exposure to arsenic at different life-stages and DNA methylation meta-analysis in buccal cells and leukocytes.

Environ Health 2021 07 9;20(1):79. Epub 2021 Jul 9.

Division of Environmental Health Sciences, School of Public Health, University of California, 2121 Berkeley Way, Room 5302, Berkeley, Berkeley, CA, 94720, USA.

Background: Arsenic (As) exposure through drinking water is a global public health concern. Epigenetic dysregulation including changes in DNA methylation (DNAm), may be involved in arsenic toxicity. Epigenome-wide association studies (EWAS) of arsenic exposure have been restricted to single populations and comparison across EWAS has been limited by methodological differences. Leveraging data from epidemiological studies conducted in Chile and Bangladesh, we use a harmonized data processing and analysis pipeline and meta-analysis to combine results from four EWAS.

Methods: DNAm was measured among adults in Chile with and without prenatal and early-life As exposure in PBMCs and buccal cells (N = 40, 850K array) and among men in Bangladesh with high and low As exposure in PBMCs (N = 32, 850K array; N = 48, 450K array). Linear models were used to identify differentially methylated positions (DMPs) and differentially variable positions (DVPs) adjusting for age, smoking, cell type, and sex in the Chile cohort. Probes common across EWAS were meta-analyzed using METAL, and differentially methylated and variable regions (DMRs and DVRs, respectively) were identified using comb-p. KEGG pathway analysis was used to understand biological functions of DMPs and DVPs.

Results: In a meta-analysis restricted to PBMCs, we identified one DMP and 23 DVPs associated with arsenic exposure; including buccal cells, we identified 3 DMPs and 19 DVPs (FDR < 0.05). Using meta-analyzed results, we identified 11 DMRs and 11 DVRs in PBMC samples, and 16 DMRs and 19 DVRs in PBMC and buccal cell samples. One region annotated to LRRC27 was identified as a DMR and DVR. Arsenic-associated KEGG pathways included lysosome, autophagy, and mTOR signaling, AMPK signaling, and one carbon pool by folate.

Conclusions: Using a two-step process of (1) harmonized data processing and analysis and (2) meta-analysis, we leverage four DNAm datasets from two continents of individuals exposed to high levels of As prenatally and during adulthood to identify DMPs and DVPs associated with arsenic exposure. Our approach suggests that standardizing analytical pipelines can aid in identifying biological meaningful signals.
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http://dx.doi.org/10.1186/s12940-021-00754-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272372PMC
July 2021

A Signature of Four Circulating microRNAs as Potential Biomarkers for Diagnosing Early-Stage Breast Cancer.

Int J Mol Sci 2021 Jun 6;22(11). Epub 2021 Jun 6.

Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon.

Breast cancer (BC) is the most predominant type of cancer among women. The aim of this study is to find new biomarkers that can help in early detection of BC, especially for those who are too young to be screened using mammography as per guidelines. Using microRNA microarray, we previously showed dysregulation of 74 microRNAs in tumors from early BC patients as compared with normal adjacent tissues, which we were interested in studying in blood circulation. In this study, we investigated the expression of 12 microRNA (miR-21/miR-155/miR-23a/miR-130a/miR-145/miR-425-5p/miR-139-5p/miR-451/miR-195/miR-125b/miR-100, and miR-182) in the plasma of 41 newly diagnosed Lebanese BC patients with early invasive ductal carcinoma as compared with 32 healthy controls. Total RNA was extracted from plasma, and expression levels of miRNA of interest were measured using RT-qPCR followed by statistical analysis; miR-21, miR-155, miR-23a, miR-130a, miR-145, miR-425-5p, and miR-139-5p were significantly upregulated and miR-451 was significantly downregulated, in the plasma of BC patients as compared with healthy controls. The positively correlated miR-23a, miR-21, and miR-130a had a high diagnostic accuracy (86%). Importantly, the combination of miR-145/miR-425-5p/miR-139-5p/miR-130a scored the highest diagnostic accuracy of 95% with AUC = 0.97 (sensitivity 97% and specificity 91%). MicroRNAs are promising non-invasive diagnostic biomarkers for early-stage BC with the panel of miR-145/miR-425-5p/miR-139-5p/miR-130a having the highest diagnostic accuracy.
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http://dx.doi.org/10.3390/ijms22116121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200990PMC
June 2021

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids.

Nat Commun 2021 06 28;12(1):3987. Epub 2021 Jun 28.

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.
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http://dx.doi.org/10.1038/s41467-021-23899-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238961PMC
June 2021

Magnesium treatment on methylation changes of transmembrane serine protease 2 (TMPRSS2).

Nutrition 2021 09 7;89:111340. Epub 2021 May 7.

Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Electronic address:

Objectives: The viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike protein priming. This study aims to test the hypothesis that magnesium (Mg) treatment leads to DNA methylation changes in TMPRSS2.

Methods: This study is nested within the Personalized Prevention of Colorectal Cancer Trial, a double-blind 2 × 2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center.

Results: We found that 12 wk of personalized Mg treatment significantly increased 5-methylcytosine methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to the placebo arm (decreased by 0.1%) in those ages < 65 y. The difference remained statistically significant after adjusting for age, sex, and baseline methylation as well as correction for false discovery rate (adjusted P = 0.014). Additionally, Mg treatment significantly reduced 5-hydroxymethylcytosine levels at cg26337277 (close proximity to TSS200 and the 5' untranslated region, promoter) by 2.3% compared to an increase of 7.1% in the placebo arm after adjusting for covariates in those ages < 65 y (P = 0.003). The effect remained significant at a false discovery rate of 0.10 (adjusted P = 0.088).

Conclusions: Among individuals ages < 65 y with calcium-to-magnesium intake ratios equal to or over 2.6, reducing the ratio to around 2.3 increased 5-methylcytosine modifications (i.e., cg16371860) and reduced 5-hydroxymethylcytosine modifications (i.e., cg26337277) in the TMPRSS2 gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention in the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the TMPRSS2 genotype.
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http://dx.doi.org/10.1016/j.nut.2021.111340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102075PMC
September 2021

DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function.

Clin Epigenetics 2021 Jun 2;13(1):121. Epub 2021 Jun 2.

Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Background: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies.

Results: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E-03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang's 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β =  - 0.12, 95% CI = [- 0.16, - 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E-08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E-06). The "first-generation" clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria.

Conclusion: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.
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http://dx.doi.org/10.1186/s13148-021-01082-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170969PMC
June 2021

Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.

Genome Med 2021 Apr 30;13(1):74. Epub 2021 Apr 30.

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.

Methods: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses.

Results: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development.

Conclusions: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.
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http://dx.doi.org/10.1186/s13073-021-00877-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088054PMC
April 2021

Epigenetically mediated electrocardiographic manifestations of sub-chronic exposures to ambient particulate matter air pollution in the Women's Health Initiative and Atherosclerosis Risk in Communities Study.

Environ Res 2021 07 22;198:111211. Epub 2021 Apr 22.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA; Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.

Background: Short-duration exposure to ambient particulate matter (PM) air pollution is associated with cardiac autonomic dysfunction and prolonged ventricular repolarization. However, associations with sub-chronic exposures to coarser particulates are relatively poorly characterized as are molecular mechanisms underlying their potential relationships with cardiovascular disease.

Materials And Methods: We estimated associations between monthly mean concentrations of PM < 10 μm and 2.5-10 μm in diameter (PM PM) with time-domain measures of heart rate variability (HRV) and QT interval duration (QT) among U.S. women and men in the Women's Health Initiative and Atherosclerosis Risk in Communities Study (n = 82,107; n = 76,711). Then we examined mediation of the PM-HRV and PM-QT associations by DNA methylation (DNAm) at three Cytosine-phosphate-Guanine (CpG) sites (cg19004594, cg24102420, cg12124767) with known sensitivity to monthly mean PM concentrations in a subset of the participants (n = 7,169; n = 6,895). After multiply imputing missing PM, electrocardiographic and covariable data, we estimated associations using attrition-weighted, linear, mixed, longitudinal models adjusting for sociodemographic, behavioral, meteorological, and clinical characteristics. We assessed mediation by estimating the proportions of PM-HRV and PM-QT associations mediated by DNAm.

Results: We found little evidence of PM-HRV association, PM-QT association, or mediation by DNAm.

Conclusions: The findings suggest that among racially/ethnically and environmentally diverse U.S. populations, sub-chronic exposures to coarser particulates may not exert appreciable, epigenetically mediated effects on cardiac autonomic function or ventricular repolarization. Further investigation in better-powered studies is warranted, with additional focus on shorter duration exposures to finer particulates and non-electrocardiographic outcomes among relatively susceptible populations.
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http://dx.doi.org/10.1016/j.envres.2021.111211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179344PMC
July 2021

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.

Am J Hum Genet 2021 05 21;108(5):874-893. Epub 2021 Apr 21.

Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206199PMC
May 2021

Risks of Macrosomia Associated with Catechol--Methyltransferase Genotypes and Genetic-Epigenetic Interactions among Children with and without Gestational Diabetes Exposure.

Child Obes 2021 07 6;17(5):365-370. Epub 2021 Apr 6.

Department of Preventive Medicine, Center for Global Oncology, Institute for Global Health, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Gestational diabetes mellitus (GDM) is a major macrosomia risk factor. Variations in the catechol--methyltransferase (COMT; rs4680) genotypes are associated with heightened susceptibility to environmental exposures and nutritional conditions. However, macrosomia risks associated with COMT genetics, epigenetics, and the interaction between genetic and epigenetics among children with and without exposure to GDM are unknown. Data from women/children pairs ( = 1087) who participated in the Tianjin Gestational Diabetes Birth Cohort were used to examine the odds of being born with macrosomia associated with COMT-genotypes, 55 CpG sites located on the COMT gene, and genetic and epigenetic interactions. Odds of macrosomia associated with COMT genetic, epigenetic, genetic and epigenetic interactions, and moderations with GDM were tested using adjusted logistic regression models. Overall, 16.1% ( = 175) of children were born with macrosomia. Models showed that children with at least one copy of the minor allele (A) had higher odds of macrosomia (odds ratio, 1.82; 95% confidence interval 1.25-2.64) compared with children with the GG-genotype. After false discovery rate corrections, none of the 55 CpG sites located on the COMT gene was associated with odds of macrosomia. The genetic and epigenetic associations were not modified by exposure to GDM. Findings suggest carriers of the COMT GG-genotype had lower odds of macrosomia, and this association was not modified by epigenetics or exposure to GDM.
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http://dx.doi.org/10.1089/chi.2020.0327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236387PMC
July 2021

Persistent variations of blood DNA methylation associated with treatment exposures and risk for cardiometabolic outcomes in long-term survivors of childhood cancer in the St. Jude Lifetime Cohort.

Genome Med 2021 04 6;13(1):53. Epub 2021 Apr 6.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 735, Memphis, TN, 38105, USA.

Background: It is well-established that cancer treatment substantially increases the risk of long-term adverse health outcomes among childhood cancer survivors. However, there is limited research on the underlying mechanisms. To elucidate the pathophysiology and a possible causal pathway from treatment exposures to cardiometabolic conditions, we conducted epigenome-wide association studies (EWAS) to identify the DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions.

Methods: We included 2052 survivors (median age 33.7 years) of European ancestry from the St. Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Cumulative doses of chemotherapy and region-specific radiation were abstracted from medical records. Seven cardiometabolic conditions were clinically assessed. DNAm profile was measured using MethylationEPIC BeadChip with blood-derived DNA.

Results: By performing multiple treatment-specific EWAS, we identified 935 5'-cytosine-phosphate-guanine-3' (CpG) sites mapped to 538 genes/regions associated with one or more cancer treatments at the epigenome-wide significance level (p < 9 × 10). Among the treatment-associated CpGs, 8 were associated with obesity, 63 with hypercholesterolemia, and 17 with hypertriglyceridemia (false discovery rate-adjusted p < 0.05). We observed substantial mediation by methylation at four independent CpGs (cg06963130, cg21922478, cg22976567, cg07403981) for the association between abdominal field radiotherapy (abdominal-RT) and risk of hypercholesterolemia (70.3%) and by methylation at three CpGs (cg19634849, cg13552692, cg09853238) for the association between abdominal-RT and hypertriglyceridemia (54.6%). In addition, three CpGs (cg26572901, cg12715065, cg21163477) partially mediated the association between brain-RT and obesity with a 32.9% mediation effect, and two CpGs mediated the association between corticosteroids and obesity (cg22351187, 14.2%) and between brain-RT and hypertriglyceridemia (cg13360224, 10.5%). Notably, several mediator CpGs reside in the proximity of well-established dyslipidemia genes: cg21922478 (ITGA1) and cg22976567 (LMNA).

Conclusions: In childhood cancer survivors, cancer treatment exposures are associated with DNAm patterns present decades following the exposure. Treatment-associated DNAm sites may mediate the causal pathway from specific treatment exposures to certain cardiometabolic conditions, suggesting the utility of DNAm sites as risk predictors and potential mechanistic targets for future intervention studies.
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http://dx.doi.org/10.1186/s13073-021-00875-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025387PMC
April 2021

DNA Methylation GrimAge and Incident Diabetes: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Diabetes 2021 06 5;70(6):1404-1413. Epub 2021 Apr 5.

Center for Global Oncology, Institute for Global Health, Northwestern University Feinberg School of Medicine, Chicago, IL

DNA methylation (DNAm)-based biological age (epigenetic age) has been suggested as a useful biomarker of age-related conditions including type 2 diabetes (T2D), and its newest iterations (GrimAge measurements) have shown early promise. In this study, we explored the association between epigenetic age and incident T2D in the context of their relationships with obesity. A total of 1,057 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were included in the current analyses. We stratified the participants into three groups: normal weight, overweight, and obese. A 1-year increase of GrimAge was associated with higher 10-year (study years 15-25) incidence of T2D (odds ratio [OR] 1.06, 95% CI 1.01-1.11). GrimAge acceleration, which represents the deviation of GrimAge from chronological age, was derived from the residuals of a model of GrimAge and chronological age, and any GrimAge acceleration (positive GrimAA: having GrimAge older than chronological age) was associated with significantly higher odds of 10-year incidence of T2D in obese participants (OR 2.57, 95% CI 1.61-4.11). Cumulative obesity was estimated by years since obesity onset, and GrimAge partially mediated the statistical association between cumulative obesity and incident diabetes or prediabetes (proportion mediated = 8.0%). In conclusion, both older and accelerated GrimAge were associated with higher risk of T2D, particularly among obese participants. GrimAge also statistically mediated the associations between cumulative obesity and T2D. Our findings suggest that epigenetic age measurements with DNAm can potentially be used as a risk factor or biomarker associated with T2D development.
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http://dx.doi.org/10.2337/db20-1167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275890PMC
June 2021

Magnesium Treatment on Methylation Changes of Transmembrane Serine Protease 2 (TMPRSS2).

medRxiv 2021 Mar 12. Epub 2021 Mar 12.

Background: The viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike (S) protein priming.

Objectives: To test the hypothesis that Mg treatment leads to DNA methylation changes in .

Methods: This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2×2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized.

Results: We found that 12-week of personalized Mg treatment significantly increased 5-mC methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to placebo arm (decreased by 0.1%) in those aged < 65 years old. The difference remained statistically significant after adjusting for age, sex and baseline methylation as well as FDR correction (FDR-adjusted =0.014). Additionally, Mg treatment significantly reduced 5-hmC level at cg26337277 (close proximity to TSS200 and 5'UTR, promoter) by 2.3% compared to increases by 7.1% in the placebo arm after adjusting for covariates in those aged < 65 years old ( =0.003). The effect remained significant at FDR of 0.10 (adjusted value=0.088).

Conclusion: Among individuals aged younger than 65 years with the Ca:Mg intake ratios equal to or over 2.6, reducing Ca:Mg ratios to around 2.3 increased 5-mC modifications (i.e. cg16371860) and reduced 5-hmC modifications (i.e. cg26337277) in the gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention for the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the genotype.
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http://dx.doi.org/10.1101/2021.03.11.21253287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987044PMC
March 2021

The presence of emphysema on chest imaging and mid-life cognition.

ERJ Open Res 2021 Jan 15;7(1). Epub 2021 Mar 15.

Minneapolis Veterans Affairs Health Care System, Minneapolis, MN, USA.

Background: Airflow obstruction is associated with cognitive dysfunction but studies have not assessed how emphysema, a structural phenotype of lung disease, might be associated with cognitive function independent from pulmonary function measured by spirometry. We aimed to determine the relationship between the presence of visually detectable emphysema on chest computed tomography (CT) imaging and cognitive function.

Methods: We examined 2491 participants, mean age of 50 years, from the Coronary Artery Risk Development in Young Adults study who were assessed for the presence of emphysema on chest CT imaging and had cognitive function measured 5 years later with a battery of six cognitive tests.

Results: Of those assessed, 172 (7%) had emphysema. After adjusting for age, sex, height, study centre, race, body mass index, education and smoking, visual emphysema was significantly associated with worse performance on most cognitive tests. Compared to those without emphysema, participants with emphysema performed worse on cognitive testing: 0.39 sd units lower (95% CI -0.53- -0.25) on the Montreal Cognitive Assessment, 0.27 sd units lower (95% CI -0.42- -0.12) on the Rey Auditory Verbal Learning Test, 0.29 sd units lower (95% CI -0.43- -0.14) on the Digit Symbol Substitution Test and 0.25 sd units lower (95% CI -0.42- -0.09) on letter fluency. Further adjustment for forced expiratory volume in 1 s (FEV), peak FEV and annualised FEV decline did not attenuate these associations.

Conclusions: The presence of emphysema on chest CT is associated with worse cognitive function, independent of airflow obstruction. These data suggest that emphysema may be a novel risk factor for cognitive impairment.
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http://dx.doi.org/10.1183/23120541.00048-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957295PMC
January 2021

Dietary factors, gut microbiota, and serum trimethylamine-N-oxide associated with cardiovascular disease in the Hispanic Community Health Study/Study of Latinos.

Am J Clin Nutr 2021 06;113(6):1503-1514

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.

Background: Trimethylamine-N-oxide (TMAO), a diet-derived and gut microbiota-related metabolite, is associated with cardiovascular disease (CVD). However, major dietary determinants and specific gut bacterial taxa related to TMAO remain to be identified in humans.

Objectives: We aimed to identify dietary and gut microbial factors associated with circulating TMAO.

Methods: This cross-sectional study included 3972 participants (57.3% women) aged 18-74 y from the Hispanic Community Health Study/Study of Latinos in the United States. Dietary information was collected by 24-h dietary recalls at baseline interview (2008-2011), and baseline serum TMAO and its precursors were measured by an untargeted approach. Gut microbiome was profiled by shotgun metagenomic sequencing in a subset of participants (n = 626) during a follow-up visit (2016-2018). Logistic and linear regression were used to examine associations of inverse-normalized metabolites with prevalent CVD, dietary intake, and bacterial species, respectively, after adjustment for sociodemographic, behavioral, and clinical factors.

Results: TMAO was positively associated with prevalent CVD (case number = 279; OR = 1.34; 95% CI: 1.17, 1.54, per 1-SD). Fish (P = 1.26 × 10-17), red meat (P = 3.33 × 10-16), and egg (P = 3.89 × 10-5) intakes were top dietary factors positively associated with TMAO. We identified 9 gut bacterial species significantly associated with TMAO (false discovery rate <0.05). All 4 species positively associated with TMAO belong to the order Clostridiales, of which 3 might have homologous genes encoding carnitine monooxygenase, an enzyme converting carnitine to trimethylamine (TMA). The red meat-TMAO association was more pronounced in participants with higher abundances of these 4 species compared with those with lower abundance (Pinteraction = 0.013), but such microbial modification was not observed for fish-TMAO or egg-TMAO associations.

Conclusion: In US Hispanics/Latinos, fish, red meat, and egg intakes are major dietary factors associated with serum TMAO. The identified potential TMA-producing gut microbiota and microbial modification on the red meat-TMAO association support microbial TMA production from dietary carnitine, whereas the fish-TMAO association is independent of gut microbiota.
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http://dx.doi.org/10.1093/ajcn/nqab001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168354PMC
June 2021

Association of cardiovascular health and epigenetic age acceleration.

Clin Epigenetics 2021 02 25;13(1):42. Epub 2021 Feb 25.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Cardiovascular health (CVH) has been defined by the American Heart Association (AHA) as the presence of the "Life's Simple 7" ideal lifestyle and clinical factors. CVH is known to predict longevity and freedom from cardiovascular disease, the leading cause of death for women in the United States. DNA methylation markers of aging have been aggregated into a composite epigenetic age score, which is associated with cardiovascular morbidity and mortality. However, it is unknown whether poor CVH is associated with acceleration of aging as measured by DNA methylation markers in epigenetic age.

Methods And Results: We performed a cross-sectional analysis of racially/ethnically diverse post-menopausal women enrolled in the Women's Health Initiative cohort recruited between 1993 and 1998. Epigenetic age acceleration (EAA) was calculated using DNA methylation data on a subset of participants and the published Horvath and Hannum methods for intrinsic and extrinsic EAA. CVH was calculated using the AHA measures of CVH contributing to a 7-point score. We examined the association between CVH score and EAA using linear regression modeling adjusting for self-reported race/ethnicity and education. Among the 2,170 participants analyzed, 50% were white and mean age was 64 (7 SD) years. Higher or more favorable CVH scores were associated with lower extrinsic EAA (~ 6 months younger age per 1 point higher CVH score, p < 0.0001), and lower intrinsic EAA (3 months younger age per 1 point higher CVH score, p < 0.028).

Conclusions: These cross-sectional observations suggest a possible mechanism by which ideal CVH is associated with greater longevity.
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http://dx.doi.org/10.1186/s13148-021-01028-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905851PMC
February 2021

Gestational Diabetes History and Glucose Tolerance After Pregnancy Associated With Coronary Artery Calcium in Women During Midlife: The CARDIA Study.

Circulation 2021 Mar 1;143(10):974-987. Epub 2021 Feb 1.

Vanderbilt University, Memphis, TN (M.W., J.J.C.).

Background: Gestational diabetes (GD) leads to earlier onset and heightened risk of type 2 diabetes, a strong risk factor for cardiovascular disease (CVD). However, it is unclear whether attaining normoglycemia can ameliorate the excess CVD risk associated with GD history. This study sought to evaluate GD history and glucose tolerance after pregnancy associated with coronary artery calcification (CAC) in women, a manifestation of atherosclerotic CVD and a predictor of CVD clinical events.

Methods: Data were obtained from the CARDIA study (Coronary Artery Risk Development in Young Adults), a US multicenter, community-based prospective cohort of young Black (50%) and White adults aged 18 to 30 years at baseline (1985-1986). The sample included 1133 women without diabetes at baseline, who had ≥1 singleton births (n=2066) during follow-up, glucose tolerance testing at baseline and up to 5 times during 25 years (1986-2011), GD status, and CAC measurements obtained from 1 or more follow up examinations at years 15, 20, and 25 (2001-2011). CAC was measured by noncontrast cardiac computed tomography; dichotomized as Any CAC (score>0) or No CAC (score=0). Complementary log-log models for interval-censored data estimated adjusted hazard ratios of CAC and 95% confidence intervals for GD history and subsequent glucose tolerance groups (normoglycemia, prediabetes, or incident diabetes) on average 14.7 years after the last birth adjusted for prepregnancy and follow-up covariates.

Results: Of 1133 women, 139 (12.3%) reported GD and were 47.6 years of age (4.8 SD) at follow-up. CAC was present in 25% (34/139) of women with GD and 15% (149/994) of women with no GD. In comparison with no GD/normoglycemia, adjusted hazard ratios (95% CIs) were 1.54 (1.06-2.24) for no GD/prediabetes and 2.17 (1.30-3.62) for no GD/incident diabetes, and 2.34 (1.34-4.09), 2.13 (1.09-4.17), and 2.02 (0.98-4.19) for GD/normoglycemia, GD/prediabetes, and GD/incident diabetes, respectively (overall =0.003).

Conclusions: Women without previous GD showed a graded increase in the risk of CAC associated with worsening glucose tolerance. Women with a history of GD had a 2-fold higher risk of CAC across all subsequent levels of glucose tolerance. Midlife atherosclerotic CVD risk among women with previous GD is not diminished by attaining normoglycemia.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940578PMC
March 2021

Childhood Risk Factors and Adulthood Cardiovascular Disease: A Systematic Review.

J Pediatr 2021 05 29;232:118-126.e23. Epub 2021 Jan 29.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Academic General Pediatrics, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.

Objective: To conduct a comprehensive review of the literature on childhood risk factors and their associations with adulthood subclinical and clinical cardiovascular disease (CVD).

Study Design: A systematic search was performed using the MEDLINE, EMBASE, PsycINFO, CINAHL, and Web of Science databases to identify English-language articles published through June 2018. Articles were included if they were longitudinal studies in community-based populations, the primary exposure occurred during childhood, and the primary outcome was either a measure of subclinical CVD or a clinical CVD event occurring in adulthood. Two independent reviewers screened determined whether eligibility criteria were met.

Results: There were 210 articles that met the predefined criteria. The greatest number of publications examined associations of clinical risk factors, including childhood adiposity, blood pressure, and cholesterol, with the development of adult CVD. Few studies examined childhood lifestyle factors including diet quality, physical activity, and tobacco exposure. Domains of risk beyond "traditional" cardiovascular risk factors, such as childhood psychosocial adversity, seemed to have strong published associations with the development of CVD.

Conclusions: Although the evidence was fairly consistent in direction and magnitude for exposures such as childhood adiposity, hypertension, and hyperlipidemia, significant gaps remain in the understanding of how childhood health and behaviors translate to the risk of adulthood CVD, particularly in lesser studied exposures like glycemic indicators, physical activity, diet quality, very early life course exposure, and population subgroups.
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http://dx.doi.org/10.1016/j.jpeds.2021.01.053DOI Listing
May 2021

Association of the V122I Transthyretin Amyloidosis Genetic Variant With Cardiac Structure and Function in Middle-aged Black Adults: Coronary Artery Risk Development in Young Adults (CARDIA) Study.

JAMA Cardiol 2020 Dec 23. Epub 2020 Dec 23.

Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Importance: The variant V122I is commonly enriched in the transthyretin (TTR) gene in individuals of African ancestry and associated with greater risk of heart failure (HF) in older adulthood, after age 65 years. Prevention of HF may be most effective earlier in life, but whether screening with echocardiography can identify subclinical cardiac abnormalities during middle age to risk-stratify individuals appears to be unknown.

Objective: To examine the association between the V122I TTR variant and cardiac structure and function during middle age in those without prevalent HF.

Design, Setting, And Participants: This serial cross-sectional study of 875 Black participants in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort was conducted at 4 urban sites across the US. Recruiting was completed in 1985-1986, and follow-up examinations occurred 25 and 30 years later. A subset of Black adults from the CARDIA cohort who underwent TTR genotyping was included. Data analysis was completed from January 2020 to October 2020.

Exposures: The V122I TTR genotype.

Main Outcomes And Measures: Echocardiographic left ventricular (LV) circumferential and longitudinal systolic strain and LV structure, measured at years 25 and 30 of follow-up. The analyses were adjusted for age, sex, echocardiography quality, genetic ancestry, and field center.

Results: Among the 875 Black adults (mean [SD] age, 49.4 [3.8] years at year 25; 543 women [62.1%]), there were 31 individuals who were heterozygous and 1 who was homozygous for the V122I TTR variant. Of the adults who had an echocardiogram at year 25, rates of hypertension (312 [46%]), diabetes (102 [15%]), and current smoking (128 [19%]) were not significantly different between those who did and did not carry V122I TTR. At year 25, there was no difference in LV circumferential strain, longitudinal strain, or LV structure between those who did vs did not carry V122I TTR. At year 30, those who carried V122I TTR had significantly lower absolute LV circumferential strain (mean [SD], 12.4 [4.2] percentage units) compared with those who did not carry the variant (mean [SD], 14.5 [3.7] percentage units). Those who carried V122I TTR also had significantly higher LV mass index values (mean [SD], 97.5 [34.1] g/m2) compared with those who did not (mean [SD], 83.7 [22.6] g/m2) at year 30.

Conclusions And Relevance: Carrier status for the V122I TTR variant is associated with subclinical cardiac abnormalities in middle age (worse LV systolic function and higher LV mass) that have been associated with increased risk of incident HF. Midlife screening of individuals who carry V122I TTR with echocardiography may prognosticate risk of symptomatic HF and inform prevention strategies.
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http://dx.doi.org/10.1001/jamacardio.2020.6623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758832PMC
December 2020
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