scholarly journals Changes in Whole-Blood microRNA Profiles during the Onset and Treatment Process of Cerebral Infarction: A Human Study

2020 ◽  
Vol 21 (9) ◽  
pp. 3107
Author(s):  
Arata Abe ◽  
Mayui Tanaka ◽  
Akihito Yasuoka ◽  
Yoshikazu Saito ◽  
Shinji Okada ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cerebral Infarction ◽  
Whole Blood ◽  
Treatment Process ◽  
Human Study ◽  
Differentially Expressed ◽  
Group A ◽  
Mirna Species ◽  
Clinical Trials Registry ◽  
Process Trial

Circulating miRNA species are promising symptom markers for various diseases, including cardiovascular disease. However, studies regarding their role in the treatment process are limited, especially concerning cerebral infarction. This study aimed to extract miRNA markers to investigate whether they reflect both onset and treatment process of cerebral infarction. A total of 22 patients (P-group) and 22 control subjects (C-group) were examined for their whole-blood miRNA profiles using DNA GeneChip™ miRNA 4.0 Array, with six patients examined after treatment (T-group). A total of 64 miRNAs were found to be differentially expressed between the C- and P-groups. Out of 64 miRNAs, the expression levels of two miRNAs correlated with hypertension. A total of 155 miRNAs were differentially expressed between the P- and T-groups. Five common miRNAs were found among the 64 and 155 miRNAs identified. Importantly, these common miRNAs were inversely regulated in each comparison (e.g., C < P > T), including miR-505-5p, which was previously reported to be upregulated in aortic stenosis patients. Our previous study using rat cerebral infarction models detected the downregulation of an apoptosis repressor, WDR26, which was repressed by one of the five miRNAs. Our results provide novel information regarding the miRNA-based diagnosis of cerebral infarction in humans. In particular, the five common miRNAs could be useful makers for the onset and the treatment process. Trial registration: This study was registered in the UMIN Clinical Trials Registry (UMIN000038321).

scholarly journals An Evaluation of Morphological Changes and Deformability of Suspended Red Blood Cells Prepared Using Whole Blood with Different Hemoglobin Levels of Tibetans

2021 ◽  
pp. 1-10
Author(s):  
Rui Zhong ◽  
Dingding Han ◽  
Xiaodong Wu ◽  
Hong Wang ◽  
Wanjing Li ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Whole Blood ◽  
Blood Cells ◽  
Morphological Changes ◽  
Osmotic Fragility ◽  
Spherical Shape ◽  
Hypoxic Environment ◽  
Wide Range ◽  
Group A ◽  
Cell Membrane Protein

Background: The hypoxic environment stimulates the human body to increase the levels of hemoglobin (HGB) and hematocrit and the number of red blood cells. Such enhancements have individual differences, leading to a wide range of HGB in Tibetans’ whole blood (WB). Study Design: WB of male Tibetans was divided into 3 groups according to different HGB (i.e., A: >120 but ≤185 g/L, B: >185 but ≤210 g/L, and C: >210 g/L). Suspended red blood cells (SRBC) processed by collected WB and stored in standard conditions were examined aseptically on days 1, 14, 21, and 35 after storage. The routine biochemical indexes, deformability, cell morphology, and membrane proteins were tested. Results: Mean corpuscular volume, adenosine triphosphate, pH, and deformability were not different in group A vs. those in storage (p > 0.05). The increased rate of irreversible morphology of red blood cells was different among the 3 groups, but there was no difference in the percentage of red blood cells with an irreversible morphology after 35 days of storage. Group C performed better in terms of osmotic fragility and showed a lower rigid index than group A. Furthermore, SDS-PAGE revealed similar cross-linking degrees of cell membrane protein but the band 3 protein of group C seemed to experience weaker clustering than that of group A as detected by Western Blot analysis after 35 days of storage. Conclusions: There was no difference in deformability or morphological changes in the 3 groups over the 35 days of storage. High HGB levels of plateau SRBC did not accelerate the RBC change from a biconcave disc into a spherical shape and it did not cause a reduction in deformability during 35 days of preservation in bank conditions.

scholarly journals OP0021 IDENTIFICATION OF DIFFERENTIALLY EXPRESSED GENES IN EARLY RHEUMATOID ARTHRITIS PATIENTS RESPONDING TO TOCILIZUMAB

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 12.2-12
Author(s):  
I. Muller ◽  
M. Verhoeven ◽  
H. Gosselt ◽  
M. Lin ◽  
T. De Jong ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
T Cells ◽  
Gene Ontology ◽  
Regulatory T Cells ◽  
Early Rheumatoid Arthritis ◽  
Whole Blood ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Double Blind

Background:Tocilizumab (TCZ) is a monoclonal antibody that binds to the interleukin 6 receptor (IL-6R), inhibiting IL-6R signal transduction to downstream inflammatory mediators. TCZ has shown to be effective as monotherapy in early rheumatoid arthritis (RA) patients (1). However, approximately one third of patients inadequately respond to therapy and the biological mechanisms underlying lack of efficacy for TCZ remain elusive (1). Here we report gene expression differences, in both whole blood and peripheral blood mononuclear cells (PBMC) RNA samples between early RA patients, categorized by clinical TCZ response (reaching DAS28 < 3.2 at 6 months). These findings could lead to identification of predictive biomarkers for TCZ response and improve RA treatment strategies.Objectives:To identify potential baseline gene expression markers for TCZ response in early RA patients using an RNA-sequencing approach.Methods:Two cohorts of RA patients were included and blood was collected at baseline, before initiating TCZ treatment (8 mg/kg every 4 weeks, intravenously). DAS28-ESR scores were calculated at baseline and clinical response to TCZ was defined as DAS28 < 3.2 at 6 months of treatment. In the first cohort (n=21 patients, previously treated with DMARDs), RNA-sequencing (RNA-seq) was performed on baseline whole blood PAXgene RNA (Illumina TruSeq mRNA Stranded) and differential gene expression (DGE) profiles were measured between responders (n=14) and non-responders (n=7). For external replication, in a second cohort (n=95 therapy-naïve patients receiving TCZ monotherapy), RNA-seq was conducted on baseline PBMC RNA (SMARTer Stranded Total RNA-Seq Kit, Takara Bio) from the 2-year, multicenter, double-blind, placebo-controlled, randomized U-Act-Early trial (ClinicalTrials.gov identifier: NCT01034137) and DGE was analyzed between 84 responders and 11 non-responders.Results:Whole blood DGE analysis showed two significantly higher expressed genes in TCZ non-responders (False Discovery Rate, FDR < 0.05): urotensin 2 (UTS2) and caveolin-1 (CAV1). Subsequent analysis of U-Act-Early PBMC DGE showed nine differentially expressed genes (FDR < 0.05) of which expression in clinical TCZ non-responders was significantly higher for eight genes (MTCOP12, ZNF774, UTS2, SLC4A1, FECH, IFIT1B, AHSP, and SPTB) and significantly lower for one gene (TND2P28M). Both analyses were corrected for baseline DAS28-ESR, age and gender. Expression of UTS2, with a proposed function in regulatory T-cells (2), was significantly higher in TCZ non-responders in both cohorts. Furthermore, gene ontology enrichment analysis revealed no distinct gene ontology or IL-6 related pathway(s) that were significantly different between TCZ-responders and non-responders.Conclusion:Several genes are differentially expressed at baseline between responders and non-responders to TCZ therapy at 6 months. Most notably, UTS2 expression is significantly higher in TCZ non-responders in both whole blood as well as PBMC cohorts. UTS2 could be a promising target for further analyses as a potential predictive biomarker for TCZ response in RA patients in combination with clinical parameters (3).References:[1]Bijlsma JWJ, Welsing PMJ, Woodworth TG, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet. 2016;388(10042):343-55.[2]Bhairavabhotla R, Kim YC, Glass DD, et al. Transcriptome profiling of human FoxP3+ regulatory T cells. Human Immunology. 2016;77(2):201-13.[3]Gosselt HR, Verhoeven MMA, Bulatovic-Calasan M, et al. Complex machine-learning algorithms and multivariable logistic regression on par in the prediction of insufficient clinical response to methotrexate in rheumatoid arthritis. Journal of Personalized Medicine. 2021;11(1).Disclosure of Interests:None declared

scholarly journals OP0286 PROTEOMICS AND RNA SEQUENCING APPROACHES HIGHLIGHT THE ROLE OF ENDOTHELIAL CELL DYSREGULATION IN IL-1 AND IFN MEDIATED AUTOINFLAMMATORY DISEASES, NOMID AND CANDLE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 178-179
Author(s):  
S. Alehashemi ◽  
M. Garg ◽  
B. Sellers ◽  
A. De Jesus ◽  
A. Biancotto ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Whole Blood ◽  
Cell Activation ◽  
Immune Cell ◽  
Differentially Expressed ◽  
Neutrophilic Dermatosis ◽  
Healthy Controls ◽  
Differentially Expressed Proteins ◽  
Rna Seq ◽  
Before And After

Background:Systemic Autoinflammatory diseases present with sterile inflammation. NOMID (Neonatal-Onset Multisystem Inflammatory Disease) is caused by gain-of-function mutations inNLRP3and excess IL-1 production, presents with fever, neutrophilic dermatosis, aseptic meningitis, hearing loss and eye inflammation; CANDLE (Chronic Atypical Neutrophilic Dermatosis, Lipodystrophy and Elevated Temperature) is caused by loss-of-function mutations in proteasome genes that lead to type-1 interferon signaling, characterized by fever, panniculitis, lipodystrophy, cytopenia, systemic and pulmonary hypertension and basal ganglia calcification. IL-1 blockers are approved for NOMID and JAK-inhibitors show efficacy in CANDLE treatment.Objectives:We used proteomic analysis to compare differentially expressed proteins in active NOMID and CANDLE compared to healthy controls before and after treatment, and whole blood bulk RNA seq to identify the immune cell signatures.Methods:Serum samples from active NOMID (n=12) and CANDLE (n=7) before and after treatment (table 1) and age matched healthy controls (HC) (n=7) were profiled using the SomaLogic platform (n=1125 proteins). Differentially expressed proteins in NOMID and CANDLE were ranked after non-parametric tests for unpaired (NOMIDp<0.05, CANDLE,p<0.1) and paired (p<0.05) analysis and assessed by enriched Gene Ontology pathways and network visualization. Whole blood RNA seq was performed (NOMID=7, CANDLE=7, Controls =5) and RPKM values were used to assess immune cells signatures.Table 1.Patient’s characteristicsNOMIDN=12, Male =6CANDLEN=7, Male =6AgeMedian (range)12 (2, 28)16 (3, 20)Ethnicity%White (Hispanic)80 (20)100 (30)GeneticsNLRP3mutation(2 Somatic, 10 Germline)mutations in proteasome component genes(1 digenic, 6 Homozygous/compound Heterozygous)Before treatmentAfter treatmentBefore treatmentAfter treatmentCRPMedian (range) mg/L52 (16-110)5 (0-23)5 (0-101)1 (0-4)IFN scoremedian (range)0NA328 (211-1135)3 (0-548)Results:Compared to control, 205 proteins (127 upregulated, 78 downregulated) were significantly different at baseline in NOMID, compared to 163 proteins (101 upregulated, and 62 downregulated) in CANDLE. 134 dysregulated proteins (85 upregulated, 49 downregulated) overlapped in NOMID and CANDLE (Figure 1). Pathway analysis identified neutrophil and monocyte chemotaxis signature in both NOMID and CANDLE. NOMID patients had neutrophilia and active neutrophils. CANDLE patients exhibited active neutrophils in whole blood RNA. Endothelial cell activation was the most prominent non-hematopoietic signature and suggest distinct endothelial cell dysregulation in NOMID and CANDLE. In NOMID, the signature included neutrophil transmigration (SELE) endothelial cell motility in response to angiogenesis (HGF, VEGF), while in CANDLE the endothelial signatures included extracellular matrix protein deposition (COL8A) suggesting increased vascular stiffness. CANDLE patients had higher expression of Renin, 4 out of 7 had hypertension, NOMID patients did not have hypertension. Treatment with anakinra and baricitinib normalized 143 and 142 of dysregulated proteins in NOMID and CANDLE respectively.Conclusion:Differentially expressed proteins in NOMID and CANDLE are consistent with innate immune cell activation. Distinct endothelial cell signatures in NOMID and CANDLE may provide mechanistic insight into differences in vascular phenotypes. Treatment with anakinra and Baricitinib in NOMID and CANDLE leaves 30% and 13% of the dysregulated proteins unchanged.Acknowledgments:This work was supported by Intramural Research atNational Institute of Allergy Immunology and Infectious Diseases of National Institutes of Health, Bethesda, Maryland, the Center of Human Immunology and was approved by the IRB.Disclosure of Interests:None declared

scholarly journals O18 Integrated molecular analysis of systemic sclerosis skin and blood shows significant differences between major autoantibody subgroups

Rheumatology ◽  
2021 ◽  
Vol 60 (Supplement_1) ◽  
Author(s):  
Kristina E Clark ◽  
Corrado Campochiaro ◽  
Eszter Csomor ◽  
Adam Taylor ◽  
Katherine Nevin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Whole Blood ◽  
Serum Markers ◽  
Differentially Expressed ◽  
Longitudinal Change ◽  
Beta Catenin ◽  
Skin Score ◽  
Topoisomerase 1 ◽  
Organ Manifestations

Abstract Background/Aims  The major antinuclear autoantibodies of systemic sclerosis (SSc) associate with different skin score trajectories and risk of internal organ manifestations. To elucidate molecular differences between ANA-defined subgroups, we utilised the prospective BIOPSY cohort of well-characterised SSc patients. Methods  The prospectively collected BIOPSY cohort recruited 52 SSc patients (21 early dcSSc, 15 established dcSSc, 16 lcSSc) and 16 healthy controls (HC). 36 (69%) of the SSc patients are female. Mean disease duration in the early dcSSc cohort was 24 months (sd 12 months), and in established dcSSc was 11.3 years. ANA frequency in BIOPSY reflected the overall dcSSc population: anti-topoisomerase-1 (ATA) n = 14 (27%), anti-RNA pol III (ARA) n = 12 (23%) and other n = 26 (50%). Mean baseline skin score (MRSS) for early dcSSc was 21 (sd 11.2). At a group level mRSS peak was 21.9 (11.8) at 3 months and fell to 19.1(10.5) at 12 months. Serum biomarkers of ECM turnover and fibrosis were measured three monthly and genome-wide transcriptomic profiling of whole skin and whole blood performed by RNA-Seq. Statistical analysis used RStudio with ANOVA, and Tukey post-hoc test. Differential gene expression used the Bioconductor limma software, with standard thresholds for significance. Results  At baseline, there were differences in soluble markers between clinical SSc sugroups and HC but not for major ANA subgroups. However, we found clear differences in early dcSSc analysed by major ANA subset for longitudinal change in serum markers of fibrosis and in whole skin gene expression, suggesting a mechanistic basis for the distinct clinical phenotypes associated with hallmark ANAs. During follow-up, significant differences were observed in HA, TIMP1, and PIIINP at 6 and 12 months (p &lt; 0.05), with stable levels in ATA+ patients compared to progressively increased levels in the other subgroups. There were 564 significantly differentially expressed genes in skin between early dcSSc and HC. Unsupervised clustering differentiated patients with ARA and ATA positivity with early dcSSc. 54 genes were significantly differentially expressed in skin between ATA and ARA patients. Whilst 179 genes were differentially expressed in whole blood between early dcSSc compared with HC, no genes could significantly differentiate ATA from ARA. Functional analysis using HALLMARK pathway analysis identified both shared pathways associated with SSc across ANA groups (e.g. TGF beta signaling, IL6 JAK STAT3 signalling, inflammatory response), and pathways only upregulated in patients with ATA (e.g. Wnt beta catenin signaling, Notch signaling), and ARA (e.g. interferon gamma response, adipogenesis). Conclusion  We have found significant differences in skin gene expression and longitudinal change in serum markers by autoantibody specificity in dcSSc. Our findings have implications for SSc pathogenesis and support stratification by ANA subgroup in clinical studies. Disclosure  K.E. Clark: None. C. Campochiaro: None. E. Csomor: Corporate appointments; employee of GSK. A. Taylor: Corporate appointments; employee of GSK. K. Nevin: Corporate appointments; employee of GSK. N. Galwey: Corporate appointments; employee of GSK. M.A. Morse: Corporate appointments; employee of GSK. V.H. Ong: None. E. Derrett-Smith: None. N. Wisniacki: Corporate appointments; employee of GSK. S. Flint: Corporate appointments; employee of GSK. C.P. Denton: Consultancies; Actelion, GlaxoSmithKline, Bayer, Sanofi, lnventiva, Boehringer Ingelheim, Roche, Bristol Myers Squibb, CSL Behring, UCB, Leadiant Biosciences, Corbus, Servier, Arxx Therapeutics.

Selection of Blood (Packed RBCs) for Transfusion in Newborn Baby up to the Age of 4 Months

2012 ◽  
Vol 1 (1) ◽  
pp. 36-40
Author(s):  
Ghulam Mostafa Khan
Keyword(s):  
Blood Group ◽  
Whole Blood ◽  
Placental Transfer ◽  
Newborn Baby ◽  
Older Children ◽  
Proper Selection ◽  
Group A ◽  
Cross Matching ◽  
Packed Rbcs ◽  
Selection Of

Proper selection of donor’s blood group is essential to prevent transfusion hazards. It is known that ABO antigen is fully developed at birth but the newborn baby does not produce ABO antibodies until 3 to 6 months of age. The ABO antibodies present in the serum of newborn babies are derived from mother’s blood due to placental transfer. So the blood group of the newborn baby is done by ABO antigen grouping (forward grouping) only, antibody grouping (reverse grouping) is not required. In case of transfusion of blood in newborn under 4 months of age, cross-matching of donor’s blood is done with the mother’s blood if it is available. We know, recipient’s same group of blood is always preferable in case of transfusion in adults or older children. But selection of blood for transfusion in the infants under 4 months of age depends on the mother’s blood group as well. If the mother’s blood group differs from the infant’s blood group, the infant’s same group of blood may not be selected for transfusion. For example, if the mother’s blood group is “O” and the newborn blood group is “A” or “B”, infant’s same group “A” or “B” group blood could not be transfused, because the anti-A & anti-B antibodies can be derived in the infant’s serum from mother’s blood which may react with the “A” or “B” antigen of the donor’s blood. In this case “O” group packed RBCs should be selected for transfusion. “O” group whole blood may contain IgG anti-A and anti-B antibodies in the plasma which can react with the “A” or “B” antigen of the infant’s blood. So to avoid anti-A & anti-B antibodies in “O” group, plasma should be discarded and the packed RBCs should be transfused. In case of Rh-negative mother with Rh positive baby, Rh antibody may develop in mother’s blood and Rh antibody may enter into baby’s circulation, in this case the infant should be transfused with Rh-negative blood to avoid Rh antigen & antibody reaction. So for the selection of blood for transfusion in newborn baby up to the age of 4 months mother’s blood group is important to select the appropriate blood. DOI: http://dx.doi.org/10.3329/jemc.v1i1.11138J Enam Med Col 2011; 1(1): 36-40

scholarly journals Whole Blood Transcriptome Analysis in Children with Sickle Cell Anemia

2022 ◽  
Vol 12 ◽  
Author(s):  
Beatrice E. Gee ◽  
Andrea Pearson ◽  
Iris Buchanan-Perry ◽  
Roger P. Simon ◽  
David R. Archer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Sequencing ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Whole Blood ◽  
Differentially Expressed ◽  
Mrna Levels ◽  
Control Subjects ◽  
Non Coding Rna ◽  
And Control

Whole transcriptome RNA-sequencing was performed to quantify RNA expression changes in whole blood samples collected from steady state sickle cell anemia (SCA) and control subjects. Pediatric SCA and control subjects were recruited from Atlanta (GA)—based hospital(s) systems and consented for RNA sequencing. RNA sequencing was performed on an Ion Torrent S5 sequencer, using the Ion Total RNA-seq v2 protocol. Data were aligned to the hg19 reference genome and analyzed in the Partek Genomics studio package (v7.0). 223 genes were differentially expressed between SCA and controls (± 1.5 fold change FDR p &lt; 0.001) and 441 genes show differential transcript expression (± 1.5 fold FDR p &lt; 0.001). Differentially expressed RNA are enriched for hemoglobin associated genes and ubiquitin-proteasome pathway genes. Further analysis shows higher gamma globin gene expression in SCA (33-fold HBG1 and 49-fold HBG2, both FDR p &lt; 0.05), which did not correlate with hemoglobin F protein levels. eQTL analysis identified SNPs in novel non-coding RNA RYR2 gene as having a potential regulatory role in HBG1 and HBG2 expression levels. Gene expression correlation identified JHDM1D-AS1(KDM7A-DT), a non-coding RNA associated with angiogenesis, enhanced GATA1 and decreased JAK-STAT signaling to correlate with HBG1 and HBG2 mRNA levels. These data suggest novel regulatory mechanisms for fetal hemoglobin regulation, which may offer innovative therapeutic approaches for SCA.

scholarly journals Plasma S1P links to hypertension and biomarkers of inflammation, metabolism and cardiovascular disease – findings from a translational investigation

2020 ◽  
Author(s):  
Amra Jujic ◽  
Frank Matthes ◽  
Lotte Vanherle ◽  
Henning Petzka ◽  
Marju Orho-Melander ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Systolic Blood Pressure ◽  
Immune Cell ◽  
Vascular Dysfunction ◽  
Plasma Concentrations ◽  
Human Study ◽  
Experimental Hypertension ◽  
Study Cohort ◽  
Markers Of Inflammation

Recent studies identified sphingosine-1-phosphate (S1P) as an important player in immune cell trafficking and vascular dysfunction contributing to the development and progression of overt hypertension. Although targeting S1P signaling revealed therapeutic potential in different experimental hypertension studies, validations of S1P-blood pressure associations in humans are lacking. In a translational approach, we explored the associations between plasma S1P, quantified using LC-MS, and blood pressure in a family-based study cohort (MOS) study, and in a longitudinally conducted murine hypertension cohort. In MOS, linear multivariate regression analyses showed that plasma S1P associates with increased systolic blood pressure. Study subjects with systolic blood pressure ≥ 140 mmHg presented with significantly higher S1P plasma concentrations compared to subjects with blood pressure ≤ 120 mmHg independent of age and sex. The S1P-blood pressure association was validated in a murine model where plasma S1P increased with systolic blood pressure. In a sub-sample of the human study population, proteomic profiling for markers of inflammation, metabolism and cardiovascular disease was carried out using proximity Extension Assays. Testing S1P associations revealed multiple significant interactions, some of them with marked sex-specificity. Amongst them, interleukin 18, which exerts apparent vascular and immune responses during hypertension and associates to adverse cardiovascular events, strongly correlates with plasma S1P concentrations in females but not males in both humans and mice. In vitro and ex vivo validation of S1P effects on endothelial and monocytic cells of murine or human origin and resistance arteries isolated from mice disclosed augmented expression of different vascular dysfunction and inflammation markers in response to exogenously added S1P. Taken together, our translational findings strongly suggest a link between plasma S1P and systolic blood pressure as well as several inflammation and cardiovascular disease biomarkers in humans, encouraging further studies to investigate S1Ps potential as a therapeutic target in hypertensive disease.

scholarly journals Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Tianxiao Huan ◽  
Roby Joehanes ◽  
Ci Song ◽  
Fen Peng ◽  
Yichen Guo ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Dna Methylation ◽  
Whole Blood ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Transcriptional Regulatory ◽  
Disease Associations ◽  
Independent Replication ◽  
Functional Mechanisms

Abstract Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.

scholarly journals Cardiovascular Disease-Related Serum Proteins in Workers Occupationally Exposed to Polycyclic Aromatic Hydrocarbons

2019 ◽  
Vol 171 (1) ◽  
pp. 235-246 ◽  
Author(s):  
Ayman Alhamdow ◽  
Christian Lindh ◽  
Maria Albin ◽  
Per Gustavsson ◽  
Håkan Tinnerberg ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Polycyclic Aromatic Hydrocarbons ◽  
Aromatic Hydrocarbons ◽  
Serum Proteins ◽  
Linear Regression Analysis ◽  
Differentially Expressed ◽  
Incidence And Mortality ◽  
Polycyclic Aromatic ◽  
Pah Exposure ◽  
Related Proteins

AbstractChimney sweeps have higher incidence and mortality of cardiovascular disease (CVD), likely related to their exposure to polycyclic aromatic hydrocarbons (PAH). In order to identify underlying mechanisms of PAH-related CVD, we here investigated whether PAH exposure was associated with levels of putative CVD-related proteins in serum among currently working chimney sweeps. We enrolled 116 chimney sweeps and 125 unexposed controls, all nonsmoking male workers from Sweden. We measured monohydroxylated PAH metabolites in urine by liquid chromatography coupled to tandem mass spectrometry and a panel of 85 proteins in serum using proximity extension assay. Linear regression analysis adjusted for age and body mass index showed that 25 proteins were differentially expressed between chimney sweeps and the controls (p < .05, adjusted for false discovery rate). Of the 25 proteins, follistatin (FS), prointerleukin-16 (IL-16), and heat shock protein beta-1 (HSP 27) showed positive associations with the monohydroxylated metabolites of PAH in a dose-response manner (p < .05). Pathway and gene ontology analyses demonstrated that the differentially expressed proteins were mainly involved in inflammatory response and immunological functions, such as leukocyte migration, cell movement of leukocytes, and adhesion of immune cells. In conclusion, we found a number of putative CVD-related proteins differentially expressed, between PAH-exposed and unexposed individuals, and mainly involved in inflammation and immune function. Our data warrant protective measures to reduce PAH exposure and longitudinal investigations of the protein profile in chimney sweeps and other occupational groups exposed to PAH.

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