Publications by authors named "Weihua Guan"

181 Publications

Sample-to-Answer Microfluidic Nucleic Acid Testing (NAT) on Lab-on-a-Disc for Malaria Detection at Point of Need.

Methods Mol Biol 2022 ;2393:297-313

Department of Electrical Engineering, Pennsylvania State University, University Park, PA, USA.

One of the grand challenges for field-deployable NATs is related to the front end of the assays-nucleic acid extraction from raw samples. The ideal nucleic acid sample preparation should be simple, scalable, and easy-to-operate. In this chapter, we present a lab-on-a-disc NAT device for sample-to-answer malaria diagnosis. The parasite DNA sample preparation and subsequent real-time LAMP detection are seamlessly integrated on a disposable single microfluidic compact disc, driven by energy-efficient, non-centrifuge-based magnetic field interactions. Each disc contains four parallel testing units, which could be configured either as four identical tests or as four species-specific tests. When configured as species-specific tests, it could identify two of the most life-threatening malaria species (P. falciparum and P. vivax). The reagent disc with a 4-plex analyzer (discussed in Chapter 1 ) is capable of processing four samples simultaneously with 40 min turnaround time. It achieves a detection limit of ~0.5 parasites/μl for whole blood, sufficient for detecting asymptomatic parasite carriers. The assay is performed with an automated device described in Chapter 14 . The combination of sensitivity, specificity, cost, and scalable sample preparation suggests the real-time fluorescence LAMP device could be particularly useful for malaria screening in field settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-0716-1803-5_16DOI Listing
January 2022

An Ultracompact Real-Time Fluorescence Loop-Mediated Isothermal Amplification (LAMP) Analyzer.

Methods Mol Biol 2022 ;2393:257-278

Department of Electrical Engineering, Pennsylvania State University, University Park, PA, USA.

Low-cost access to the highly sensitive and specific detection of the pathogen in the field is a crucial attribute for the next generation point-of-care (POC) platforms. In this work, we developed a real-time fluorescence nucleic acid testing device with automated and scalable sample preparation capability for field malaria diagnosis. The palm-sized battery-powered analyzer equipped with a disposable microfluidic reagent compact disc described in the companion Chap. 16 which facilitates four isothermal nucleic acid tests in parallel from raw blood samples to answer. The platform has a user-friendly interface such as touchscreen LCD and smartphone data connectivity for on-site and remote healthcare delivery, respectively. The chapter mainly focuses on describing integration procedures of the real-time fluorescence LAMP analyzer and the validation of its subsystems. The device cost is significantly reduced compared to the commercial benchtop real-time machine and other existing POC platforms. As a platform technology, self-sustainable, portable, low-cost, and easy-to-use analyzer design should create a new paradigm of molecular diagnosis toward a variety of infectious diseases at the point of need.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-0716-1803-5_14DOI Listing
January 2022

Assessing the Potential Impact of Land Use on Carbon Storage Driven by Economic Growth: A Case Study in Yangtze River Delta Urban Agglomeration.

Int J Environ Res Public Health 2021 Nov 13;18(22). Epub 2021 Nov 13.

School of Geographic and Oceanographic Sciences, Nanjing University, Nanjing 210023, China.

Economic development and land-use change can strongly affect terrestrial ecosystems' carbon balance. This paper quantifies the changes in land use of Yangtze River Delta urban agglomeration (YRD) in 2020 and 2035 under three economic growth scenarios, exploring the concurrent impact on carbon storage. The results showed that the land carbon storage of YRD had decreased by 1453.80 Tg in 2000-2020, and will continue to decrease by 982.38 Tg, 1417.62 Tg, and 1636.21 Tg under the scenarios of a slow, medium, and rapid economic growth from 2020 to 2035, respectively. The large-scale occupation of cultivated land and woodland for construction land caused by economic development and population growth was an important reason. The occupation of cultivated land by construction land in Nanjing, Shanghai, and its surrounding areas had further intensified, while the reduction in carbon storage caused by the reduction in woodland had become more prominent in Hangzhou, Shaoxing, Jinhua, and the surrounding areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph182211924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624101PMC
November 2021

Gene expression of oxidative stress markers and lung function: A CARDIA lung study.

Mol Genet Genomic Med 2021 Nov 19:e1832. Epub 2021 Nov 19.

Department of Pathology and Laboratory Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA.

Background: Circulating markers of oxidative stress have been associated with lower lung function. Our objective was to study the association of gene expression levels of oxidative stress pathway genes (ALOX12, ALOX15, ARG2, GSTT1, LPO, MPO, NDUFB3, PLA2G7, and SOD3) and lung function forced expiratory volume in one second (FEV ), forced vital capacity (FVC) in Coronary Artery Risk Development in Young Adults study.

Methods: Lung function was measured using spirometry and the Nanostring platform was used to estimate gene expression levels. Linear regression models were used to study association of lung function measured at year 30, 10-year decline in lung function and gene expression after adjustment for center, smoking, and BMI, measured at year 25.

Results: The 10-year decline of FEV was faster in highest NDUFB3 quartile compared to the lowest (difference = -2.09%; p = 0.001) after adjustment for multiple comparisons. The 10-year decline in FEV and FVC was nominally slower in highest versus lowest quartile of PLA2G7 (difference = 1.14%; p = 0.02, and difference = 1.06%; p = 0.005, respectively). The other genes in the study were not associated with FEV or FVC.

Conclusion: Higher gene expression levels in oxidative stress pathway genes are associated with faster 10-year FEV decline.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1832DOI Listing
November 2021

Rapid detection of novel coronavirus SARS-CoV-2 by RT-LAMP coupled solid-state nanopores.

Biosens Bioelectron 2021 Nov 2;197:113759. Epub 2021 Nov 2.

Department of Electrical Engineering, Pennsylvania State University, University Park, PA, 16802, United States; Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, 16802, United States. Electronic address:

The current pandemic of COVID-19 caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) has raised significant public health concerns. Rapid and accurate testing of SARS-CoV-2 is urgently needed for early detection and control of the disease spread. Here, we present an RT-LAMP coupled glass nanopore digital counting method for rapid detection of SARS-CoV-2. We validated and compared two one-pot RT-LAMP assays targeting nucleocapsid (N) and envelop (E) genes. The nucleocapsid assay was adopted due to its quick time to positive and better copy number sensitivity. For qualitative positive/negative classification of a testing sample, we used the glass nanopore to digitally count the RT-LAMP amplicons and benchmarked the event rate with a threshold. Due to its intrinsic single molecule sensitivity, nanopore sensors could capture the amplification dynamics more rapidly (quick time to positive). We validated our RT-LAMP coupled glass nanopore digital counting method for SARS-CoV-2 detection by using both spiked saliva samples and COVID-19 clinical nasopharyngeal swab samples. The results obtained showed excellent agreement with the gold standard RT-PCR assay. With its integration capability, the electronic nanopore digital counting platform has significant potential to provide a rapid, sensitive, and specific point-of-care assay for SARS-CoV-2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bios.2021.113759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560184PMC
November 2021

Decomposition Process of Nonoxidative Microwave Radiation Roasting of a Mixed Rare Earth Concentrate with Sodium Carbonate.

ACS Omega 2021 Oct 13;6(42):28119-28130. Epub 2021 Oct 13.

State Key Laboratory of Baiyunobo Rare Earth Resource Researches and Comprehensive Utilization, Baotou Research Institute of Rare Earths, Inner Mongolia, Baotou 014030, China.

This article introduces an efficient decomposition process that uses sodium carbonate (NaCO) and activated carbon (C) as additives to decompose Bayan Obo mixed rare earth concentrate (hereinafter to be referred to as RE concentrate) by nonoxidative microwave radiation roasting. The roasting temperature, holding time, and contents of NaCO and activated carbon are investigated. The optimum process parameters for decomposition are 800 °C and 30 min. The ratio of m(NaCO)/m(RE concentrate) is 0.5, and the ratio of m(C)/m (ER concentrate and NaCO) is 0.2 based on experimental data. Under the above conditions, the decomposition rate (shortened to DR) of RE concentrate is 98.58%, and the removal rates (shortened to CRs) of fluorine (F) and phosphorus (P) reached 80.35 and 46.75%, respectively. These rates are higher than traditional oxidation roasting under the same conditions. The three reasons for the result are the unique microwave heating characteristics, the overall efficient reaction of the mixture (RE concentrate, NaCO, and activated carbon), and the high nonoxidation rate of cerium. For these reasons and large experimental data, the reaction rate of the mixture is improved, and the efficiency of dilute hydrochloric acid for leaching rare earth elements is enhanced. In this article, the valence of rare earth elements in the roasted ore is all in the form of trivalence. Importantly, this nonoxidative roasted product can avoid the generation of chlorine in hydrochloric acid leaching. Moreover, such a short holding time is scarce in traditional roasting. When the mixture was roasted by utilizing microwave heating, the sinter phenomenon of the roasted product was avoided at high-temperature roasting. Finally, the surface morphology of RE concentrate at different conditions was observed by scanning electron microscopy (SEM) analysis, which can be used to compare the specific differences of roasting methods. According to these results, this process is beneficial for the decomposition of RE concentrate in terms of NaCO roasting and is helpful for improving the clean and green technology method of hydrometallurgy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.1c04194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552337PMC
October 2021

A Multi-Marker Test for Analyzing Paired Genetic Data in Transplantation.

Front Genet 2021 13;12:745773. Epub 2021 Oct 13.

Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.

Emerging evidence suggests that donor/recipient matching in non-HLA (human leukocyte antigen) regions of the genome may impact transplant outcomes and recognizing these matching effects may increase the power of transplant genetics studies. Most available matching scores account for either single-nucleotide polymorphism (SNP) matching only or sum these SNP matching scores across multiple gene-coding regions, which makes it challenging to interpret the association findings. We propose a multi-marker Joint Score Test (JST) to jointly test for association between recipient genotype SNP effects and a gene-based matching score with transplant outcomes. This method utilizes Eigen decomposition as a dimension reduction technique to potentially increase statistical power by decreasing the degrees of freedom for the test. In addition, JST allows for the matching effect and the recipient genotype effect to follow different biological mechanisms, which is not the case for other multi-marker methods. Extensive simulation studies show that JST is competitive when compared with existing methods, such as the sequence kernel association test (SKAT), especially under scenarios where associated SNPs are in low linkage disequilibrium with non-associated SNPs or in gene regions containing a large number of SNPs. Applying the method to paired donor/recipient genetic data from kidney transplant studies yields various gene regions that are potentially associated with incidence of acute rejection after transplant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.745773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548646PMC
October 2021

Maternal caffeine intake and DNA methylation in newborn cord blood.

Am J Clin Nutr 2021 Oct 20. Epub 2021 Oct 20.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

Background: Epigenetic mechanisms may underlie associations between maternal caffeine consumption and adverse childhood metabolic outcomes. However, limited studies have examined neonate DNA methylation (DNAm) patterns in the context of preconception or prenatal exposure to caffeine metabolites.

Objective: We examined preconception and pregnancy caffeine exposure with DNAm alterations in neonate cord blood (n = 378).

Design: In a secondary analysis of the Effects of Aspirin in Gestation and Reproduction Trial (EAGeR), we measured maternal caffeine, paraxanthine, and theobromine concentrations from stored serum collected preconception (on average 2 months before pregnancy) and at 8 weeks of gestation. In parallel, self-reported caffeinated beverage intake was captured via administration of questionnaires and daily diaries. We profiled DNAm from the cord blood buffy coat of singletons using the MethylationEPIC BeadChip. We assessed associations of maternal caffeine exposure and methylation β-values using multivariable robust linear regression. A false discovery rate (FDR) correction was applied using the Benjamini-Hochberg method.

Results: In preconception the majority of women reported consuming one or fewer servings/day on average and caffeine and paraxanthine metabolite levels were 88 and 36 µmol/L, respectively. Preconception serum caffeine metabolites were not associated with individual CpG sites (FDR > 5%), though pregnancy theobromine was associated with DNAm at cg09460369 near RAB2A (β = 0.028; SE = 0.005; FDR P = 0.012). Preconception self-reported caffeinated beverage intake compared to no intake was associated with DNAm at cg09002832 near GLIS3 (β = -0.013; SE = 0.002; FDR P = 0.036). No associations with self-reported intake during pregnancy were found.

Conclusions: Few effects of maternal caffeine exposure on neonate methylation differences in leukocytes were identified in this relatively low caffeine consumption population.Clinical Trial Registry: #NCT00467363.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcn/nqab348DOI Listing
October 2021

Longitudinal change in blood DNA epigenetic signature after smoking cessation.

Epigenetics 2021 Oct 6:1-12. Epub 2021 Oct 6.

Pulmonary Center, Boston University School of Medicine, Boston, MA, USA.

Cigarette smoking is associated with epigenetic changes that may be reversible following smoking cessation. Whole blood DNA methylation was evaluated in Framingham Heart Study Offspring (n = 169) and Third Generation (n = 30) cohort participants at two study visits 6 years apart and in Atherosclerosis Risk in Communities (ARIC) study (n = 222) participants at two study visits 20 years apart. Changes in DNA methylation (delta β values) at 483,565 cytosine-phosphate-guanine (CpG) sites and differentially methylated regions (DMRs) were compared between participants who were current, former, or never smokers at both visits (current-current, former-former, never-never, respectively), versus those who quit in the interim (current-former). Interim quitters had more hypermethylation at four CpGs annotated to , one CpG annotated to , and one intergenic CpG (cg21566642) compared with current-current smokers (FDR < 0.02 for all), and two significant DMRs were identified. While there were no significant differentially methylated CpGs in the comparison of interim quitters and former-former smokers, 106 DMRs overlapping with small nucleolar RNA were identified. As compared with all non-smokers, current-current smokers additionally had more hypermethylation at two CpG sites annotated to and , respectively, and another intergenic CpG (cg14339116). Gene transcripts associated with smoking cessation were implicated in immune responses, cell homoeostasis, and apoptosis. Smoking cessation is associated with early reversion of blood DNA methylation changes at CpG sites annotated to and towards those of never smokers. Associated gene expression suggests a role of longitudinal smoking-related DNA methylation changes in immune response processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15592294.2021.1985301DOI Listing
October 2021

Detection of SARS-CoV-2 with Solid-State CRISPR-Cas12a-Assisted Nanopores.

Nano Lett 2021 10 20;21(19):8393-8400. Epub 2021 Sep 20.

Department of Electrical Engineering, Pennsylvania State University, University Park, Pennsylvania 16802, United States.

The outbreak of the SARS-CoV-2 caused the disease COVID-19 to spread globally. Specific and sensitive detection of SARS-CoV-2 facilitates early intervention and prevents the disease from spreading. Here, we present a solid-state CRISPR-Cas12a-assisted nanopore (SCAN) sensing strategy for the specific detection of SARS-CoV-2. We introduced a nanopore-sized counting method to measure the cleavage ratio of reporters, which is used as a criterion for positive/negative classification. A kinetic cleavage model was developed and validated to predict the reporter size distributions. The model revealed the trade-offs between sensitivity, turnaround time, and false-positive rate of the SARS-CoV-2 SCAN. With preamplification and a 30 min CRISPR Cas12a assay, we achieved excellent specificity against other common human coronaviruses and a limit of detection of 13.5 copies/μL (22.5 aM) of viral RNA at a confidence level of 95%. These results suggested that the SCAN could provide a rapid, sensitive, and specific analysis of SARS-CoV-2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.nanolett.1c02974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491552PMC
October 2021

Whole-Genome Differentially Hydroxymethylated DNA Regions among Twins Discordant for Cardiovascular Death.

Genes (Basel) 2021 07 29;12(8). Epub 2021 Jul 29.

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Epigenetics is a mechanism underlying cardiovascular disease. It is unknown whether DNA hydroxymethylation is prospectively associated with the risk for cardiovascular death independent of germline and common environment. Male twin pairs middle-aged in 1969-1973 and discordant for cardiovascular death through December 31, 2014, were included. Hydroxymethylation was quantified in buffy coat DNA collected in 1986-1987. The 1893 differentially hydroxymethylated regions (DhMRs) were identified after controlling for blood leukocyte subtypes and age among 12 monozygotic (MZ) pairs (Benjamini-Hochberg False Discovery Rate < 0.01), of which the 102 DhMRs were confirmed with directionally consistent log-fold changes and < 0.01 among additional 7 MZ pairs. These signature 102 DhMRs, independent of the germline, were located on all chromosomes except for chromosome 21 and the Y chromosome, mainly within/overlapped with intergenic regions and introns, and predominantly hyper-hydroxymethylated. A binary linear classifier predicting cardiovascular death among 19 dizygotic pairs was identified and equivalent to that generated from MZ via the 2D transformation. Computational bioinformatics discovered pathways, phenotypes, and DNA motifs for these DhMRs or their subtypes, suggesting that hydroxymethylation was a pathophysiological mechanism underlying cardiovascular death that might be influenced by genetic factors and warranted further investigations of mechanisms of these signature regions in vivo and in vitro.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes12081183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392630PMC
July 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23899-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238961PMC
June 2021

Nanofluidic charged-coupled devices for controlled DNA transport and separation.

Nanotechnology 2021 Jun 3;32(34). Epub 2021 Jun 3.

Department of Electrical Engineering, Pennsylvania State University, University Park, PA 16802, United States of America.

Controlled molecular transport and separation is of significant importance in various applications. In this work, we presented a novel concept of nanofluidic molecular charge-coupled device (CCD) for controlled DNA transport and separation. By leveraging the unique field-effect coupling in nanofluidic systems, the nanofluidic molecular CCD aims to store charged biomolecules such as DNAs in discrete regions in nanochannels and transfer and separate these biomolecules as a charge packet in a bucket brigade fashion. We developed a quantitative model to capture the impact of nanochannel surface charge, gating voltage and frequency, molecule diffusivity, and gating electrode geometry on the transport and separation efficiency. We studied the synergistic effects of these factors to guide the device design and optimize the DNA transport and separation in a nanofluidic CCD. The findings in this study provided insight into the rational design and implementation of the nanofluidic molecular CCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/1361-6528/ac027fDOI Listing
June 2021

Process Optimization and Modeling of Microwave Roasting of Bastnasite Concentrate Using Response Surface Methodology.

ACS Omega 2021 Apr 9;6(15):10486-10496. Epub 2021 Apr 9.

State Key Laboratory of Baiyunobo Rare Earth Resource Researches and Comprehensive Utilization, Baotou Research Institute of Rare Earths, Baotou 014030, Inner Mongolia, China.

The investigation of the dielectric properties of bastnasite concentrate has critical directing centrality for the microwave roasting process of bastnasite concentrate. The dielectric properties are correlated with information such as thermogravimetry-differential scanning calorimetry and temperature rise curves. This combination permits a targeted study of the mechanism of the microwave roasting process, providing new evidence about the unique conditions of this microwave roasting process. This work also explores the response surface methodology based on a central composite design to optimize the microwave non-oxidative roasting process. Single-factor tests were conducted to determine the suitable range of factors such as the content of activated carbon, holding time, and roasting temperature. The interactions between parameters were investigated through the analysis of variance method. It was indicated that the models are available to navigate the design space. Also, the optimal roasting temperature, content of activated carbon, and holding time were 1100 °C, 20%, and 21.5 min, respectively. Under these conditions, the decomposition rate of bastnasite concentrate (hereinafter to be referred as DRBC) and the oxidation rate of cerium (hereinafter to be referred as ORC) was 99.8% and less than 0.3%, respectively. The new non-oxidizing roasting method significantly shortens the roasting time, reduces the energy consumption, and has great significance for industrial applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.1c01218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153756PMC
April 2021

Performance of novel low-density lipoprotein-cholesterol calculation methods in predicting clinical and subclinical atherosclerotic cardiovascular disease risk: The Multi-Ethnic Study of Atherosclerosis.

Atherosclerosis 2021 06 8;327:1-4. Epub 2021 May 8.

Department of Pathology and Laboratory Medicine, University of Minnesota, Twin Cities, USA. Electronic address:

Background And Aims: This study examined the performance of two novel low-density lipoprotein-cholesterol (LDL-C) calculations, LDL and LDL, on predicting atherosclerotic cardiovascular diseases (ASCVD) risk compared to traditional LDL according to the 2018 American Heart Association/American College of Cardiology (AHA/ACC) primary prevention guidelines.

Methods: A total of 6701 randomly recruited Multi-Ethnic Study of Atherosclerosis (MESA) participants free of ASCVD at baseline were followed for ASCVD during a median of 13.9 years and for subclinical ASCVD-coronary artery calcium (CAC) during a median of 12.5 years. Prevalence of borderline high triglyceride (≥1.7 mmol/L) was 15.2% and was at 13.5% for high triglyceride (≥2.3 mmol/L).

Results: Applying the criteria of LDL-C<1.8 mmol/L in 40-75 year olds without diabetes mellitus to be exempt from risk discussion, LDL and LDL classified less individuals in this category than LDL (p < 0.001), both had 20 individuals with ASCVD, versus 22 by LDL. Positive CAC in the discussion-exempt group were over 38% higher (p < 0.001) when classified by LDL than by LDL or LDL. Individuals with LDL-C≥4.9 mmol/L are recommended to high-intensity statin therapy by the AHA/ACC guidelines. The LDL≥4.9 mmol/L group had 20 ASCVD events, versus 21 in LDL and 22 in LDL group.

Conclusions: In a multi-ethnic USA population, LDL and LDL did not over- or under-estimate ASCVD risk compared to LDL in primary prevention according to AHA/ACC guidelines, while LDL under-estimated subclinical ASCVD risk in the low-risk population. These findings support the replacement of LDL by LDL or LDL for lipid screen in the general population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2021.04.018DOI Listing
June 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2021.111211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179344PMC
July 2021

Conception by fertility treatment and offspring deoxyribonucleic acid methylation.

Fertil Steril 2021 08 3;116(2):493-504. Epub 2021 Apr 3.

Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Albany, New York.

Objective: To investigate whether deoxyribonucleic acid (DNA) methylation at birth and in childhood differ by conception using assisted reproductive technologies (ART) or ovulation induction compared with those in children conceived without fertility treatment.

Design: Upstate KIDS is a matched exposure cohort which oversampled on newborns conceived by treatment.

Setting: New York State (excluding New York City).

Patient(s): This analysis included 855 newborns and 152 children at approximately 9 years of age.

Intervention(s): None.

Main Outcome Measure(s): DNA methylation levels were measured using the Illumina EPIC platform. Single CpG and regional analyses at imprinting genes were conducted.

Result(s): Compared to no fertility treatment, ART was associated with lower mean DNA methylation levels at birth in 11 CpGs (located in/near SYCE1, SPRN, KIAA2013, MYO1D, GET1/WRB-SH4BGR, IGF1R, SORD, NECAB3/ACTL10, and GET1) and higher mean methylation level in 1 CpG (KLK4; all false discovery rate P<.05). The strongest association (cg17676129) was located at SYCE1, which codes for a synaptonemal complex that plays a role in meiosis and therefore infertility. This CpG remained associated with newborn hypomethylation when the analysis was limited to those conceived with ICSI, but this may be because of underlying male infertility. In addition, nine regions in maternally imprinted genes (IGF1R, PPIEL, SVOPL GNAS, L3MBTL, BLCAP, HYMAI/PLAGL1, SNU13, and MEST) were observed to have decreased mean DNA methylation levels among newborns conceived by ART. In childhood, hypomethylation of the maternally imprinted gene, GNAS, persisted. No CpGs or regions were associated with ovulation induction.

Conclusion(s): ART but not ovulation induction was associated with hypomethylation at birth, but only one difference at an imprinting region appeared to persist in childhood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fertnstert.2021.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349775PMC
August 2021

On Stochastic Reduction in Laser-Assisted Dielectric Breakdown for Programmable Nanopore Fabrication.

ACS Appl Mater Interfaces 2021 Mar 11;13(11):13383-13391. Epub 2021 Mar 11.

Department of Electrical Engineering, Pennsylvania State University, University Park, Pennsylvania 16802, United States.

The controlled dielectric breakdown emerged as a promising alternative toward accessible solid-state nanopore fabrication. Several prior studies have shown that laser-assisted dielectric breakdown could help control the nanopore position and reduce the possibility of forming multiple pores. Here, we developed a physical model to estimate the probability of forming a single nanopore under different combinations of the laser power and the electric field. This model relies on the material- and experiment-specific parameters: the Weibull statistical parameters and the laser-induced photothermal etching rate. Both the model and our experimental data suggest that a combination of a high laser power and a low electric field is statistically favorable for forming a single nanopore at a programmed location. While this model relies on experiment-specific parameters, we anticipate it could provide the experimental insights for nanopore fabrication by the laser-assisted dielectric breakdown method, enabling broader access to solid-state nanopores and their sensing applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.0c23106DOI Listing
March 2021

Plasma ω-3 and ω-6 PUFA Concentrations and Risk of Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis.

J Nutr 2021 06;151(6):1479-1486

Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.

Background: Current literature examining the prospective relation of circulating omega-3 (n-3) and omega-6 (n-6) PUFAs and atrial fibrillation (AF) is limited to predominantly white populations.

Objectives: We investigated the association of circulating n-3 and n-6 PUFAs with incident AF in participants from the Multi-Ethnic Study of Atherosclerosis.

Methods: A total of 6229 participants (mean age = 62 y; 53% female; 39% white, 27% black, 22% Hispanic, and 12% Chinese) who were free of baseline AF and with plasma phospholipid PUFAs measured at baseline using GC were prospectively followed for the development of AF. Incident AF was ascertained using International Classification of Diseases-9 codes from hospital discharge records and Medicare claims data with follow-up through 2014. Multivariable Cox proportional hazards regression analysis was performed to determine the risk of incident AF.

Results: During a median follow-up of 12.9 y, 813 (13%) participants developed AF. Each higher SD increment in arachidonic acid (AA; 20:4n-6) concentrations was associated with an 11% decreased risk of incident AF (HR: 0.89; 95% CI: 0.82, 0.96). Similarly, higher overall n-6 PUFA concentrations were also associated with a reduced AF risk (HR per SD increment: 0.93; 95% CI: 0.87, 1.00). Although no significant overall associations were observed for any individual n-3 PUFAs, higher circulating concentrations of DHA (22:6n-3) and EPA (20:5n-3) were associated with a decreased AF risk in blacks and Hispanics (DHA only) but not whites or Chinese Americans.

Conclusions: In a multiethnic cohort of individuals free of baseline cardiovascular disease, higher plasma concentrations of n-6 PUFAs, particularly AA, were associated with a reduced risk of incident AF. Important differences in AF risk were also noted across race/ethnicity for the n-3 PUFAs DHA and EPA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jn/nxab016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243886PMC
June 2021

n-3 Fatty Acid Biomarkers and Incident Type 2 Diabetes: An Individual Participant-Level Pooling Project of 20 Prospective Cohort Studies.

Diabetes Care 2021 05 3;44(5):1133-1142. Epub 2021 Mar 3.

Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: Prospective associations between n-3 fatty acid biomarkers and type 2 diabetes (T2D) risk are not consistent in individual studies. We aimed to summarize the prospective associations of biomarkers of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis.

Research Design And Methods: For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed in each cohort following a prespecified protocol, and cohort-specific associations were pooled using inverse variance-weighted meta-analysis.

Results: A total of 16,693 incident T2D cases were identified during follow-up (median follow-up ranging from 2.5 to 21.2 years). In pooled multivariable analysis, per interquintile range (difference between the 90th and 10th percentiles for each fatty acid), EPA, DPA, DHA, and their sum were associated with lower T2D incidence, with hazard ratios (HRs) and 95% CIs of 0.92 (0.87, 0.96), 0.79 (0.73, 0.85), 0.82 (0.76, 0.89), and 0.81 (0.75, 0.88), respectively (all < 0.001). ALA was not associated with T2D (HR 0.97 [95% CI 0.92, 1.02]) per interquintile range. Associations were robust across prespecified subgroups as well as in sensitivity analyses.

Conclusions: Higher circulating biomarkers of seafood-derived n-3 fatty acids, including EPA, DPA, DHA, and their sum, were associated with lower risk of T2D in a global consortium of prospective studies. The biomarker of plant-derived ALA was not significantly associated with T2D risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc20-2426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132316PMC
May 2021

Precision Dosing for Tacrolimus Using Genotypes and Clinical Factors in Kidney Transplant Recipients of European Ancestry.

J Clin Pharmacol 2021 08 26;61(8):1035-1044. Epub 2021 Feb 26.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.

Genetic variation in the CYP3A4 and CYP3A5 (CYP3A4/5) genes, which encode the key enzymes in tacrolimus metabolism, is associated with tacrolimus clearance and dose requirements. Tacrolimus has a narrow therapeutic index with high intra- and intersubject variability, in part because of genetic variation. High tacrolimus clearance and low trough concentration are associated with a greater risk for rejection, whereas high troughs are associated with calcineurin-induced toxicity. The objective of this study was to develop a model of tacrolimus clearance with a dosing equation accounting for genotypes and clinical factors in adult kidney transplant recipients of European ancestry that could preemptively guide dosing. Recipients receiving immediate-release tacrolimus for maintenance immunosuppression from 2 multicenter studies were included. Participants in the GEN03 study were used for tacrolimus model development (n = 608 recipients) and was validated by prediction performance in the DeKAF Genomics study (n = 1361 recipients). Nonlinear mixed-effects modeling was used to develop the apparent oral tacrolimus clearance (CL/F) model. CYP3A4/5 genotypes and clinical covariates were tested for their influence on CL/F. The predictive performance of the model was determined by assessing the bias (median prediction error [ME] and median percentage error [MPE]) and the precision (root median squared error [RMSE]) of the model. CYP3A5*3, CYP3A4*22, corticosteroids, calcium channel blocker and antiviral drug use, age, and diabetes significantly contributed to the interindividual variability of oral tacrolimus apparent clearance. The bias (ME, MPE) and precision (RMSE) of the final model was good, 0.49 ng/mL, 6.5%, and 3.09 ng/mL, respectively. Prospective testing of this equation is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcph.1823DOI Listing
August 2021

CRISPR-based detection of SARS-CoV-2: A review from sample to result.

Biosens Bioelectron 2021 Apr 21;178:113012. Epub 2021 Jan 21.

Department of Electrical Engineering, Pennsylvania State University, University Park, PA, 16802, United States; Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, 16802, United States. Electronic address:

The current pandemic of the 2019 novel coronavirus (COVID-19) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) has raised significant public health concern. Rapid, affordable, and accurate diagnostics of SARS-CoV-2 is essential for early treatment and control of the disease spread. In the past few years, CRISPR technology has shown great potential for highly sensitive and specific molecular diagnostics. Amid the ongoing COVID-19 pandemic, there is an increasing interest in implementing CRISPR-based diagnostic principles to develop fast and precise methods for detecting SARS-CoV-2. In this work, we reviewed and summarized these CRISPR-based diagnostic systems as well as their characteristics and challenges. We also provided future perspectives of CRISPR-based sensing towards point-of-care molecular diagnosis applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bios.2021.113012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826142PMC
April 2021

Plasma omega-3 and saturated fatty acids are differentially related to pericardial adipose tissue volume across race/ethnicity: the Multi-ethnic Study of Atherosclerosis.

Eur J Clin Nutr 2021 08 4;75(8):1237-1244. Epub 2021 Jan 4.

Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN, USA.

Background: Pericardial adipose tissue (PAT) is a cardiometabolic risk factor influenced by race/ethnicity, inflammation, and metabolic dysfunction. Omega-3 fatty acids (FAs) and saturated FAs (SFAs) are known to affect these latter phenomena and may influence PAT accumulation. We aimed to determine whether plasma levels of these FAs are related to PAT volume and its rate of change over a median 3-year follow-up.

Methods: Cardiac computed tomography assessed PAT in 6785 Multi-Ethnic Study of Atherosclerosis participants. Gas chromatography flame-ionization estimated plasma phospholipid FAs. Regression analyses estimated associations of FAs with PAT volume and its rate of change with adjustments for other risk factors. Race-interactions were tested.

Results: In cross-section, top tertiles of omega-3 FAs and odd-chained SFAs were associated with 2.8 and 4.93 cm lower PAT volumes, respectively; race/ethnicity was a significant modifying variable (p < 0.002). Even-chained SFAs were associated with 3.5 cm greater PAT volume. With stratification by race/ethnicity, Chinese Americans in the top tertile of omega-3 FAs showed 10.5 cm greater PAT volume than those in the referent tertile. Black individuals in the top tertile of odd-chained SFAs showed 5.0 cm lower PAT compared to referents. Black and Chinese Americans in top tertiles of even-chained SFAs showed respective 3.7 and 5.9 cm greater PAT volumes compared to referents. Two associations were observed in prospective analyses among Caucasians; race interactions were non-significant.

Conclusions: Cross-sectional and prospective findings provide inconclusive evidence as to whether plasma FAs are related to PAT in healthy individuals. Cohort studies with longer follow-up periods are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41430-020-00833-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254815PMC
August 2021

Perfluorooctanoic acid (PFOA) or perfluorooctane sulfonate (PFOS) and DNA methylation in newborn dried blood spots in the Upstate KIDS cohort.

Environ Res 2021 03 30;194:110668. Epub 2020 Dec 30.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6710B Rockledge Drive, Bethesda, MD, 20892, United States. Electronic address:

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are persistent organic pollutants which may alter prenatal development, potentially through epigenetic modifications. Prior studies examining PFOS/PFOA and DNA methylation have relatively few subjects (n < 200) and inconsistent results. We examined relations of PFOA/PFOS with DNA methylation among 597 neonates in the Upstate KIDS cohort study. PFOA/PFOS were quantified in newborn dried blood spots (DBS) using high-performance liquid chromatography/tandem mass spectrometry. DNA methylation was measured using the Infinium MethylationEPIC BeadChip with DNA extracted from DBS. Robust linear regression was used to examine the associations of PFOA/PFOS with DNA methylation at individual CpG sites. Covariates included sample plate, estimated cell type, epigenetically derived ancestry, infant sex and plurality, indicators of maternal socioeconomic status, and prior pregnancy loss. In supplemental analysis, we restricted the analysis to 2242 CpG sites previously identified as Correlated Regions of Systemic Interindividual Variation (CoRSIVs) which include metastable epialleles. At FDR<0.05, PFOA concentration >90th percentile was related to DNA methylation at cg15557840, near SCRT2, SRXN1; PFOS>90th percentile was related to 2 CpG sites in a sex-specific manner (cg19039925 in GVIN1 in boys and cg05754408 in ZNF26 in girls). When analysis was restricted to CoRSIVs, log-scaled, continuous PFOS concentration was related to DNA methylation at cg03278866 within PTBP1. In conclusion, there was limited evidence of an association between high concentrations of PFOA/PFOS and DNA methylation in newborn DBS in the Upstate KIDS cohort. These findings merit replication in populations with a higher median concentration of PFOA/PFOS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2020.110668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946760PMC
March 2021

Community-based intervention effects on older adults' physical activity and falls: Protocol and rationale for a randomized optimization trial (Ready Steady3.0).

Contemp Clin Trials 2021 02 5;101:106238. Epub 2020 Dec 5.

University of Minnesota, Psychology, 75 East River Road, Minneapolis, MN 55455, USA. Electronic address:

The Ready Steady 3.0 trial is designed to test the main and interactive effects of two behavior change intervention components, within an 8-week physical activity intervention, on older adults' physical activity (PA). Each component is comprised of behavior change strategies that emphasize two different evidence-based ways to motivate older adults to be active: interpersonal and intrapersonal. 308 adults ≥70 years old will be randomized to 1 of 4 conditions in a 2 × 2 full factorial trial in which the two factors represent the receipt (No, Yes) of interpersonal or intrapersonal behavior change strategies. Participants will also receive two core intervention components: the Otago Exercise Program adapted for small groups and a PA monitor. Interventions across conditions will be delivered during 8 weekly, small group, meetings in community settings. The primary outcome of PA, measured objectively, and secondary outcomes of falls and the quality of life will be assessed at baseline and post-intervention: 1 week, 6 months, and 12 months. Findings will enable the identification of behavior change content that contributes to physical activity outcomes within a physical activity intervention for older adults. This study is one of the first to use the MOST framework to guide the development of a community-based physical activity intervention for older adults to reduce the public health problems of low PA and falls. The results will enable the optimization of behavior change content within a PA intervention for older adults and, in turn, other PA interventions for older adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cct.2020.106238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266260PMC
February 2021

Nonoxidative Microwave Radiation Roasting of Bastnasite Concentrate and Kinetics of Hydrochloric Acid Leaching Process.

ACS Omega 2020 Oct 8;5(41):26710-26719. Epub 2020 Oct 8.

State Key Laboratory of Baiyunobo Rare Earth Resource Researches and Comprehensive Utilization, Baotou Research Institute of Rare Earths, Inner Mongolia, Baotou 014030, China.

Herein, a new clean extraction technology for the decomposition of bastnasite concentrate by utilizing the microwave radiation is proposed, which prevented Ce(III) from being oxidized to its tetravalent form. The process includes microwave radiation roasting to nonoxidatively decompose the bastnasite concentrate, mechanism analysis of Ce(III) not being oxidized to Ce(IV), hydrochloric acid leaching of the nonoxidative roasted ore, and kinetics analysis of the leaching process. The experiments were carried out concentrating on the effect of roasting temperature and holding time on the decomposition rate of the bastnasite concentrate and the oxidation rate of cerium and the effect of acidity, liquid-solid ratio, leaching temperature, and stirring rate on the leaching kinetics of the nonoxidative roasting ore. When the roasting temperature is 1100 °C, the holding time is 20 min, and the (C)/(REFCO) ratio is 0.2, the results show that the leaching efficiency of rare earths can reach 85.45% under the conditions 3 mol/L HCl, 90 °C, 60 min, 9 mL/g liquid-solid ratio, and 300 rpm stirring rate. The X-ray diffraction and scanning electron microscopy analyses of the samples before and after acid leaching show that the rare earth oxides were completely leached and Ce(III) was not oxidized to its tetravalent form. The apparent activation energies of leaching rare earths were calculated as 14.326 kJ/mol, and the HCl leaching process can be described by a new variant of the shrinking-core model, in which both the interfacial transfer and the diffusion through the product layer influenced the reaction rate. Furthermore, a semiempirical rate equation was created to describe the leaching process of the nonoxidative roasted ore.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.0c03641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581269PMC
October 2020

Methylome-wide association study of central adiposity implicates genes involved in immune and endocrine systems.

Epigenomics 2020 09 9;12(17):1483-1499. Epub 2020 Sep 9.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist-to-hip ratio and waist-to-height ratio adjusted for body mass index, in 2684 African-American adults in the Atherosclerosis Risk in Communities study. We validated significantly associated cytosine-phosphate-guanine methylation sites (CpGs) among adults using the Women's Health Initiative and Framingham Heart Study participants (combined n = 5743) and generalized associations in adolescents from The Raine Study (n = 820). We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and two in adolescents, including CpG site associations near , ,  and that had not previously been associated with obesity-related traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/epi-2019-0276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923253PMC
September 2020

Joint testing of donor and recipient genetic matching scores and recipient genotype has robust power for finding genes associated with transplant outcomes.

Genet Epidemiol 2020 11 11;44(8):893-907. Epub 2020 Aug 11.

Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Genetic matching between transplant donor and recipient pairs has traditionally focused on the human leukocyte antigen (HLA) regions of the genome, but recent studies suggest that matching for non-HLA regions may be important as well. We assess four genetic matching scores for use in association analyses of transplant outcomes. These scores describe genetic ancestry distance using identity-by-state, or genetic incompatibility or mismatch of the two genomes and therefore may reflect different underlying biological mechanisms for donor and recipient genes to influence transplant outcomes. Our simulation studies show that jointly testing these scores with the recipient genotype is a powerful method for preliminary screening and discovery of transplant outcome related single nucleotide polymorphisms (SNPs) and gene regions. Following these joint tests with marginal testing of the recipient genotype and matching score separately can lead to further understanding of the biological mechanisms behind transplant outcomes. In addition, we present results of a liver transplant data analysis that shows joint testing can detect SNPs significantly associated with acute rejection in liver transplant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.22349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658035PMC
November 2020

Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals.

Aging (Albany NY) 2020 07 22;12(14):14092-14124. Epub 2020 Jul 22.

Section General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02215, USA.

DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality ( < 9.3x10) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to , and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to , and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes () linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.103408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425458PMC
July 2020
-->