Biology subjects

Tardif, J.-C.

Publications and source records attributed to Tardif, J.-C..

16 recordsLinked to original sources

bioRxiv2026

CETP alternative splicing variation impacts human traits

The cholesteryl ester transfer protein (CETP) is an important protein in reverse cholesterol transport and has been identified as a significant factor associated with cardiovascular disease (CVD), making it a widely studied pharmaceutical target. Three protein-coding isoforms of CETP exist, distinguished by the alternative splicing of one exon each. The isoform primarily responsible for cholesterol-related functions in the plasma is well studied, but specific functions of each isoform remain poorly understood. In this study, we demonstrate the significance of considering CETPs isoforms in analyses of human traits. Using bulk RNA-seq data from multiple tissues, we characterized the expression patterns and genetic regulation determinants of CETP transcripts. Leveraging publicly available GWAS summary statistics, we conducted multivariable Mendelian Randomisation (MVMR) to estimate the impact of variation in isoform proportions on phenotypes, highlighting the importance of CETPs isoforms in pituitary and thyroid glands. Furthermore, we uncovered tissue-specific associations between CETPs isoforms and CVD-associated phenotypes. Additionally, we observed that the epistatic interaction previously reported between CETP and ADCY9, a gene implicated in modulating a CETP modulators response, may be mediated through the regulation of alternative splicing of exon 9. Our results underscore the importance of a comprehensive understanding of CETPs isoforms, which can significantly impact both fundamental and clinical research efforts.

genetics↗

bioRxiv2025

Manganese homeostasis modulates glucan and chitin unmasking in the opportunistic yeast Candida albicans

Candida albicans is a commensal fungus and also the most prevalent human fungal pathogen. The ability of this opportunistic yeast to acquire and maintain homeostatic levels of manganese (Mn), particularly in the metal-limited host environment, is an important determinant of its fitness. Recent studies have underscored the importance of Mn acquisition through members of Smf transporters, in C. albicans virulence and its ability to withstand various stresses. In the present study, we undertook transcriptional profiling in the mutant of the Mn transporter Smf12 under restricted Mn availability to identify processes that are directly affected in defective Mn uptake. Our analysis revealed that smf12 displayed a transcriptional pattern suggestive of a cell wall defect, with many transcripts associated with cell wall biogenesis being differentially regulated. smf12 together with smf11, a mutant of the closest homolog of Smf12, exhibited hypersensitivity to cell wall stressors and an altered cell wall ultrastructure. The smf mutants also exhibited unmasking of both {beta}-glucan and chitin, which unexpectedly resulted in a decreased rate of phagocytosis by macrophages, suggesting impaired recognition or internalization--an observation that challenges the prevailing paradigm. Furthermore, we showed that Mn-mediated unmasking of {beta}-glucan required modulation of glucanase activity and was not mediated through the calcineurin pathway. This study uncovers a novel role for Mn in maintaining cell wall integrity and modulating the exposure of fungal antigenic determinants, further emphasizing the critical role of this metal in supporting the opportunistic nature of C. albicans.

microbiology↗

bioRxiv2024

Insights into Heart Failure Metabolite Markersthrough Explainable Machine Learning

Understanding molecular traits through metabolomics offers an avenue to tailor cardiovascular prevention, diagnosis and treatment strategies more effectively. This study focuses on the application of machine learning (ML) and explainable artificial intelligence (XAI) algorithms to detect discriminant molecular signatures in heart failure (HF). In this study, we aim to uncover metabolites with significant predictive value by analyzing targeted metabolomics data through ML models and XAI methodologies. After robust quality control procedures, we analyzed 55 metabolites from 124 plasma samples, including 53 HF patients and 71 controls, comparing Logistic Regression (Logit) models with Support Vector Machine (SVM) and eXtreme Gradient Boosting (XGB), all achieving high accuracy in predicting group labels: 84.20% ({sigma} =5.46), 85.73% ({sigma} =6.25), and 84.80% ({sigma} =7.84), respectively. Permutation-based variable importance and Local Interpretable Model-agnostic Explanations (LIME) were used for group-level and individual-level explainability, respectively, complemented by H-Friedman statistics for variable interactions, yielding reliable, explainable insights of the ML models. Metabolites well-known for their association with heart failure, such as glucose and cholesterol, but also more recently described association such C18:1 carnitine, were reaffirmed in our analysis. The novel discovery of lignoceric acid (C24:0 fatty acid) as a critical discriminator, was confirmed in a replication cohort, underscoring its potential as a metabolite marker. Furthermore, our study highlights the utility of 2-way variable interaction analysis in unveiling a network of metabolite interactions essential for accurate disease prediction. The results demonstrate our approachs efficacy in identifying key metabolites and their interactions, illustrating the power of ML and XAI in advancing personalized healthcare solutions. See Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/616718v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@d50da1org.highwire.dtl.DTLVardef@171d4d7org.highwire.dtl.DTLVardef@4c8aaaorg.highwire.dtl.DTLVardef@123c1ed_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Low-dose colchicine treatment improves vasorelaxation, reduces arterial remodeling and attenuates blood pressure increases in spontaneously hypertensive rats

Colchicine, a microtubule depolymerizing agent, is an effective therapy for the secondary prevention of cardiovascular disease and has been approved recently as a novel treatment for atherosclerosis associated with coronary artery disease. Hypertension is a leading cause of cardiovascular disease, yet the impact of colchicine on hypertension has not been studied. We hypothesized that low-dose colchicine could be used to treat hypertension to reduce cardiovascular disease risk. The aim of this study was to administer daily, low dose (0.05 mg/kg/day) oral colchicine for 4 weeks to spontaneously hypertensive rats (SHR) and normotensive controls (WKY) and determine the effect on blood pressure, vascular reactivity, remodeling and inflammation, and left ventricular hypertrophy. Daily blood pressure measurements recorded by telemetry in conscious rats showed colchicine prevented increases in mean arterial pressure observed in the SHRs receiving vehicle over the 4-week treatment period. After the 4-weeks of treatment, 3rd order mesenteric artery vasorelaxations to isoproterenol, sodium nitroprusside and the Kv7.2-5 channel activator, ML213, were enhanced in the SHRs receiving colchicine compared to vehicle. The improved isoproterenol-mediated relaxation was also observed in WKY rats receiving colchicine, and in both the SHR and WKY, this improved effect was attenuated by the {beta}2 adrenoceptor antagonist, ICI118,551. Proteomic analysis of the mesenteric arteries by mass spectrometry revealed that colchicine treatment prevented changes observed when comparing the SHR vehicle group with the WKY vehicle group in proteins associated with extracellular matrix pathways. Immunostaining of 3rd order mesenteric arteries with Sirius red found that colchicine treatment attenuated the increased media thickness of the artery wall observed in SHRs receiving vehicle. Multiplex immunoassay and Western blots revealed colchicine reduced certain inflammatory mediators in the wall of the SHR mesenteric arteries, particularly the nucleotide-binding domain and leucine-rich repeat pyrin containing protein-3 (NLRP3), IL-18, CXCL10, and CXCL2, as well as reducing phosphorylated STAT3. Finally, in the left ventricle of the SHR, colchicine treatment attenuated a number of inflammatory mediators, including NLRP3, IL-1{beta}, and IL-18, and reduced fibrosis and cell size, which are indicative of left ventricular hypertrophy. Overall, we show colchicine has the potential to elicit cardiovascular protective effects in hypertension by targeting multiple cell types.

physiology↗

bioRxiv2023

ERK3 Is Involved in Regulating Cardiac Fibroblast Function

ERK3/MAPK6, an atypical MAPK, activates MAP kinase-activated protein kinase (MK)-5 in selected cell types. MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in Col1a1 mRNA in response to increased cardiac afterload. In addition, MK5 deficiency alters cardiac fibroblast function. This study was to determine the effect of reduced ERK3 on cardiac hypertrophy following transverse aortic constriction (TAC) and fibroblast biology. Three wk post-surgery, ERK3, but not ERK4 or p38, was co-immunoprecipitated with MK5 from both sham and TAC heart lysates. The increase in left ventricular mass and myocyte diameter was lower in TAC-ERK3+/- than TAC-ERK3+/+ hearts, whereas ERK3 haploinsufficiency did not alter systolic or diastolic function. Furthermore, the TAC-induced increase in Col1a1 mRNA abundance was diminished in ERK3+/- hearts. ERK3 immunoreactivity was detected in atrial and ventricular fibroblasts but not myocytes. In both quiescent fibroblasts and activated myofibroblasts isolated from adult mouse heart, siRNA-mediated knockdown of ERK3 reduced the TGF-{beta}-induced increase in Col1a1 mRNA. In addition, intracellular type 1 collagen immunoreactivity was reduced following ERK3 depletion in quiescent fibroblasts but not myofibroblasts. Finally, knocking down ERK3 impaired motility in both atrial and ventricular myofibroblasts. These results suggest that ERK3 plays an important role in multiple aspects of cardiac fibroblast biology.

cell biology↗

bioRxiv2023

MK2 deficiency decreases mortality during the inflammatory phase after myocardial infarction in mice

BackgroundAltering the onset, intensity, or duration of inflammation can impact the recovering hearts structure and function following myocardial infarction (MI). Substrates of MAP kinase-activated protein kinase 2 (MK2) include proteins that regulate the stability of AU-rich transcripts, including those of several pro-inflammatory cytokines. This study was to determine if MK2-deficiency impaired the inflammatory phase of post-MI wound repair. Methods and ResultsMyocardial infarctions were induced by permanent ligation of the left anterior descending coronary artery in 12-week-old male MK2+/+ and MK2-/- littermate mice. Five days post-MI, survival was 100% in MI-MK2-/- (n = 20) and 79% in MI-MK2+/+ mice (n = 29; Mandel-Cox test: P < 0.05). Area at risk and infarct size were similar. Echocardiographic imaging revealed that both systolic and diastolic LV diameters were greater in MI-MK2+/+ than MI-MK2-/- mice. MK2-deficiency did not affect the increase in wall motion score index. Infiltration of neutrophils or monocytes did not differ significantly. Cytokine and chemokine transcripts were quantified in infarcted and non-infarcted LV tissue using qPCR arrays (QIAGEN). Three days post-MI, Ifna2 was increased and Il16 was decreased in infarcted tissue from MK2-/- hearts, compared with infarcted MK2+/+ tissue, whereas in the non-infarcted MK2-/- myocardium Il27 increased and Tnfsf11, Ccl3, and Il1rn were decreased. Five days post-MI, Ctf16 and Il10 increased in infarcted MK2-/- tissue whereas in the non-infarcted MK2-/- myocardium Ccl9, Nodal, and Xcl2 increased and Il15 decreased. ConclusionsThe findings of this study suggest MK2-deficiency is an advantage during the inflammatory phase of cardiac wound repair post-MI. Clinical PerspectiveWhat is new? -The effects of MAP kinase-activated protein kinase 2 (MK2) deficiency on survival, cardiac structure and function, and the inflammatory phase of wound healing following myocardial infarction were assessed using a constitutive, pan MK2-null mouse model. -MK2-deficiency reduced mortality but did not alter area at risk or infarct size post-myocardial infarction. Inflammatory cell infiltration was also unaffected. -MK2-deficiency altered the abundance of several cytokines (increased, decreased) in infarcted and non-infarcted myocardium post-MI. What are the clinical implications? -The initial phase of wound repair post-MI involves inflammation. -The risk of damage to the myocardium and mortality may be reduced by inhibition of MK2 activity during the inflammatory phase of wound healing post-MI.

physiology↗

bioRxiv2021

Lower Aβ-PET signal in white matter lesions relates to higher extracellular free water in mixed small vessel disease and Alzheimer's pathology

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (A{beta}-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered A{beta}-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to A{beta}-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in A{beta}-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in A{beta}-PET related more closely to higher cortical A{beta} (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and A{beta}-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.

neuroscience↗

bioRxiv2021

Deep Bayesian networks for uncertainty estimation and adversarial resistance of white matter hyperintensity segmentation

White matter hyperintensities (WMH) are frequently observed on structural neuroimaging of elderly populations and are associated with cognitive decline and increased risk of dementia. Many existing WMH segmentation algorithms produce suboptimal results in populations with vascular lesions or brain atrophy, or require parameter tuning and are computationally expensive. Additionally, most algorithms do not generate a confidence estimate of segmentation quality, limiting their interpretation. MRI-based segmentation methods are often sensitive to acquisition protocols, scanners, noise-level, and image contrast, failing to generalize to other populations and out-of-distribution datasets. Given these concerns, we propose a novel Bayesian 3D Convolutional Neural Network (CNN) with a U-Net architecture that automatically segments WMH, provides uncertainty estimates of the segmentation output for quality control and is robust to changes in acquisition protocols. We also provide a second model to differentiate deep and periventricular WMH. 432 subjects were recruited to train the CNNs from four multi-site imaging studies. A separate test set of 158 subjects was used for evaluation, including an unseen multi-site study. We compared our model to two established state-of-the-art techniques (BIANCA and DeepMedic), highlighting its accuracy and efficiency. Our Bayesian 3D U-Net achieved the highest Dice similarity coefficient of 0.89 {+/-} 0.08 and the lowest modified Hausdorff distance of 2.98 {+/-} 4.40 mm. We further validated our models highlighting their robustness on clinical adversarial cases simulating data with low signal-to-noise ratio, low resolution, and different contrast (stemming from MRI sequences with different parameters). Our pipeline and models are available at: https://hypermapp3r.readthedocs.io

neuroscience↗

bioRxiv2021

A sex-specific evolutionary interaction between ADCY9 and CETP

Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of positive selection in several human populations. Furthermore, we identified a variant in CETP, rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population. The signal is mainly seen in males, a sex-specific result that is replicated in the LIMAA cohort of over 3,400 Peruvians. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues, which also differs between males and females. We also detected interaction effects of the two SNPs with sex on cardiovascular phenotypes in the UK Biobank, in line with the sex-specific genotype associations found in Peruvians at these loci. We propose that ADCY9 and CETP coevolved during recent human evolution due to sex-specific selection, which points towards a biological link between dalcetrapibs pharmacogene ADCY9 and its therapeutic target CETP.

genetics↗

bioRxiv2020

Expression, subcellular localization, and phosphorylation of MK5 in adult cardiac ventricular fibroblasts

MAP kinase-activated protein kinase-5 (MK5) plays an important role in cardiac fibroblast function. Although p38 MAPK and atypical MAPKs and ERK3 and ERK4 have been identified as activators of MK5, the kinases that activate MK5 remain controversial. Here we examined the expression, subcellular distribution, and regulation of MK5 in cardiac ventricular myofibroblasts and myocytes. The copy numbers for MK5 and ERK4 mRNA were comparable in myocytes and myofibroblasts, whereas that of ERK3 was much higher in myofibroblasts. Interestingly, MK5 and ERK3 immunoreactivity was detected in myofibroblasts but not myocytes whereas ERK4 immunoreactivity was detected in myocytes: treating in myocytes with a proteasome inhibitor or hypertrophic agonists failed to rescue MK5 immunoreactivity. In myofibroblasts, MK5 and ERK3 immunoreactivity was predominantly nuclear and cytosolic, respectively. In serum-starved cardiac myofibroblasts, phosphothreonine-182 MK5 (pT182-MK5) immunoreactivity was predominantly nuclear but increased in intensity and relocated to the cytoplasm in response to serum, sorbitol, angiotensin II, TGF{beta}, or H2O2 and this was prevented by inhibition of p38/{beta}. Phos-tag SDS-PAGE revealed multiple slower migrating bands of MK5 immunoreactivity, indicating phosphorylation of MK5 at multiple sites. Phos-tag PAGE also revealed MK5 phosphorylation was increased with fibroblast activation and in hearts exposed to a chronic increase in afterload. MK5 and ERK3 co-immunoprecipitated and proximity ligation assays revealed ERK3 and MK5 in close proximity in myofibroblast cytoplasmic compartment. Furthermore, p38/{beta} inhibition decreased the abundance of MK5 immunoreactivity in ERK3 immunoprecipitates. Finally, deleting MK5 did not reduce the abundance of ERK3 immunoreactivity. These observations suggest that p38 and/or p38{beta} are the primary mediators of T182-MK5 phosphorylation and hence MK5 activation in cardiac myofibroblasts.

biochemistry↗

bioRxiv2020

Improved segmentation of the intracranial and ventricular volumes in populations with cerebrovascular lesions and atrophy using 3D CNNs

Successful segmentation of the total intracranial vault (ICV) and ventricles is of critical importance when studying neurodegeneration through neuroimaging. We present iCVMapper and VentMapper, robust algorithms that use a convolutional neural network (CNN) to segment the ICV and ventricles from both single and multi-contrast MRI data. Our models were trained on a large dataset from two multi-site studies (N=528 subjects for ICV, N=501 for ventricular segmentation) consisting of older adults with varying degrees of cerebrovascular lesions and atrophy, which pose significant challenges for most segmentation approaches. The models were tested on 238 participants, including subjects with vascular cognitive impairment and high white matter hyperintensity burden. Two of the three test sets came from studies not used in the training dataset. We assessed our algorithms relative to four state-of-the-art ICV extraction methods (MONSTR, BET, Deep Extraction, FreeSurfer), as well as a ventricular segmentation tool (FreeSurfer). Our multi-contrast models outperformed other methods across all evaluation metrics, with average Dice coefficients of 0.98 and 0.94 for ICV and ventricular segmentation respectively. Both models were also the most time efficient, segmenting the structures in orders of magnitude faster than some of the other available methods. Our networks showed an increased accuracy with the use of a conditional random field (CRF) as a post-processing step. We further validated both segmentation models, highlighting their robustness to images with lower resolution and signal-to-noise ratio, compared to tested techniques. The pipeline and models are available at: https://icvmapp3r.readthedocs.io and https://ventmapp3r.readthedocs.io to enable further investigation of the roles of ICV and ventricles in relation to normal aging and neurodegeneration in large multi-site studies.

neuroscience↗

bioRxiv2020

MK2-deficient mice are bradycardic and display delayed hypertrophic remodelling in response to a chronic increase in afterload

MAP kinase-activated protein kinase-2 (MK2) is protein serine/threonine kinase activated by p38/{beta}. Herein we examined the cardiac phenotype of pan MK2-null (MK2-/-) mice. Survival curves for male MK2+/+ and MK2-/- mice did not differ (Mantel-Cox test, P = 0.580). At 12-weeks of age, MK2-/- mice exhibited normal systolic function along with signs of possible early diastolic dysfunction; however, ageing was not associated with an abnormal reduction in diastolic function. Both R-R interval and P-R segment durations were prolonged in MK2-deficient mice. However, heart rates normalized when isolated hearts were perfused ex vivo in working mode. Ca2+ transients evoked by field stimulation or caffeine were similar in ventricular myocytes from MK2+/+ and MK2-/- mice. MK2-/- mice had lower body temperature and an age-dependent reduction in body weight. mRNA levels of key metabolic genes, including Ppargc1a, Acadm, Lipe, and Ucp3 were increased in hearts from MK2-/- mice. For equivalent respiration rates, mitochondria from MK2-/- hearts showed a significant decrease in Ca2+-sensitivity to mitochondrial permeability transition pore (mPTP) opening. Finally, the pressure overload-induced increase in heart weight/tibia length and decrease in systolic function were attenuated in MK2-/- mice two weeks, but not eight weeks, after constriction of the transverse aorta. Collectively, these results implicate MK2 in (i) autonomic regulation of heart rate, (ii) cardiac mitochondrial function, and (iii) the early stages of myocardial remodeling in response to chronic pressure overload. Key points summaryThe cardiac characterization of pan MK2-null mice showed: O_LIaltered autonomic regulation of heart rate C_LIO_LIincreased expression of key metabolic genes C_LIO_LIdecreased Ca2+-sensitivity for MPTP opening C_LIO_LIdelayed hypertrophic remodeling in response to increased afterload C_LI

physiology↗

bioRxiv2019

Protein Tyrosine Phosphatase 1B Regulates MicroRNA-208b-Argonaute 2 Association and Thyroid Hormone Responsiveness in Cardiac Hypertrophy

Elevated reactive oxygen species (ROS) production plays an important role in the pathogenesis of several diseases, including cardiac hypertrophy. While the regulation of diverse sources of ROS is well characterized in the heart, the redox-sensitive targets that contribute to redox signaling remain largely undefined. We now report that protein tyrosine phosphatase 1B (PTP1B) is reversibly oxidized and inactivated in hearts undergoing hypertrophy and that gene deletion of PTP1B in mouse hearts cause an hypertrophic phenotype that is critically exacerbated in mice subjected to pressure overload. Furthermore, we show that PTP1B dephosphorylates Tyr393 on argonaute 2, a key component of the RNA-induced silencing complex, and sustains gene silencing in the heart. Our results indicate that PTP1B inactivation and argonaute 2 Tyr393 phosphorylation specifically prevents argonaute 2 from interacting with miR-208b. Phosphorylation and inactivation of argonaute 2 in PTP1B cKO mice revealed a mechanism by which defective miR-208b-mediated repression of thyroid hormone receptor-associated protein 1 (THRAP1/MED13) contributes to thyroid hormone-mediated cardiac hypertrophy. In support of this conclusion, inhibiting the synthesis of triiodothyronine (T3), using propylthiouracil, rescued TAC-induced hypertrophy and improved myocardial contractility and systolic function in PTP1B cKO mice. Together, our data illustrate that PTP1B activity exerts a cardioprotective effect in the heart and that redox signaling is tightly linked to thyroid hormone responsiveness and to microRNA-mediated gene silencing in pathological hypertrophy.

cell biology↗

bioRxiv2019

Inherited chromosomally integrated HHV-6 demonstrates tissue-specific RNA expression in vivo that correlates with increased antibody immune response.

Human herpesvirus-6A and 6B (HHV-6A, HHV-6B) are human viruses capable of chromosomal integration. Approximately 1% of the human population carry one copy of HHV-6A/B integrated into every cell in their body, referred to as inherited chromosomally integrated human herpesvirus 6A/B (iciHHV-6A/B). Whether iciHHV-6A/B is transcriptionally active in vivo and how it shapes the immunological response is still unclear. Here, we screened DNA-Seq and RNA-Seq data for 650 individuals available through the Genotype-Tissue Expression (GTEx) project and identified 2 iciHHV-6A and 4 iciHHV-6B positive candidates. When corresponding tissue-specific gene expression signatures were analyzed, low levels HHV-6A/B gene expression was found across multiple tissues, with the highest levels of gene expression in the brain (specifically for iciHHV-6A), testis, esophagus, and adrenal gland. U90 and U100 were the most highly expressed HHV-6 genes in both iciHHV-6A and iciHHV-6B individuals. To assess whether tissue-specific gene expression from iciHHV-6A/B influences the immune response, a cohort of 15,498 subjects was screened and 85 iciHHV-6A/B+ subjects were identified. Plasma samples from iciHHV-6A/B+ and age and sex matched controls were analyzed for antibodies to control antigens (CMV, EBV, FLU) or HHV-6A/B antigens. Our results indicate that iciHHV-6A/B+ subjects have significantly more antibodies against the U90 gene product (IE1) relative to non-iciHHV-6 individuals. Antibody responses against EBV and FLU antigens or HHV-6A/B gene products either not expressed or expressed at low levels, such as U47, U57 or U72, were identical between controls and iciHHV-6A/B+ subjects. CMV seropositive individuals with iciHHV-6A/B+ have more antibodies against CMV pp150, relative to CMV seropositive controls. These results argue that spontaneous gene expression from integrated HHV-6A/B leads to an increase in antigenic burden that translates into a more robust HHV-6A/B specific antibody response.\n\nImportanceHHV-6A/B are human herpesviruses that have the unique property of being able to integrate into the subtelomeric regions of human chromosomes. Approximately 1% of the worlds population carries integrated HHV-6A/B genome in every cell of their body. Whether viral genes are transcriptionally active in these individuals is unclear. By taking advantage of a unique tissue-specific gene expression dataset, we show the majority of tissues from iciHHV-6 individuals do not show HHV-6 gene expression. Brain and testes showed the highest tissue-specific expression of HHV-6 genes in two separate datasets. Two HHV-6 genes, U90 (immediate early 1 protein) and U100 (glycoproteins Q1 and Q2), were found to be selectively and consistently expressed across several human tissues. Expression of U90 translates into an increase in antigen-specific antibody response in iciHHV-6A/B+ subjects relative to controls. Future studies will be needed to determine the mechanism of gene expression, the effects of these genes on human gene transcription networks and the pathophysiological impact of having increased viral protein expression in tissue in conjunction with increased antigen-specific antibody production.

genomics↗

bioRxiv2019

Validation of genome-wide polygenic risk scores for coronary artery disease in French Canadians

Coronary artery disease (CAD) represents one of the leading causes of morbidity and mortality worldwide. Given the healthcare risks and societal impacts associated with CAD, their clinical management would benefit from improved prevention and prediction tools. Polygenic risk scores (PRS) based on an individuals genome sequence are emerging as potentially powerful biomarkers to predict the risk to develop CAD. Two recently derived genome-wide PRS have shown high specificity and sensitivity to identify CAD cases in European-ancestry participants from the UK Biobank. However, validation of the PRS predictive power and transferability in other populations is now required to support their clinical utility. We calculated both PRS (GPSCAD and metaGRSCAD) in French-Canadian individuals from three cohorts totaling 3639 prevalent CAD cases and 7382 controls, and tested their power to predict prevalent, incident and recurrent CAD. We also estimated the impact of the founder French-Canadian familial hypercholesterolemia deletion (LDLR delta > 15kb deletion) on CAD risk in one of these cohorts and used this estimate to calibrate the impact of the PRS. Our results confirm the ability of both PRS to predict prevalent CAD comparable to the original reports (area under the curve (AUC) = 0.72-0.84). Furthermore, the PRS identified about 6-7% of individuals at CAD risk similar to carriers of the LDLR delta > 15kb mutation, consistent with previous estimates. However, the PRS did not perform as well in predicting incident (AUC= 0.56 - 0.60) or recurrent (AUC= 0.56 - 0.60) CAD. This result suggests that additional work is warranted to better understand how ascertainment biases and study design impact PRS for CAD. Collectively, our results confirm that novel, genome-wide PRS are able to predict CAD in French-Canadians; with further improvements, this is likely to pave the way towards more targeted strategies to predict and prevent CAD-related adverse events.

genetics↗

bioRxiv2017

A Comprehensive Evaluation of the Genetic Architecture of Sudden Cardiac Arrest

BackgroundSudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. While several risk factors are observationally associated with SCA, the genetic architecture of SCA in the general population remains unknown. Furthermore, understanding which risk factors are causal may help target prevention strategies.\n\nMethodsWe carried out a large genome-wide association study (GWAS) for SCA (n=3,939 cases, 25,989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA.\n\nResultsNo variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (1) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (2) height and BMI, and (3) electrical instability traits (QT and atrial fibrillation), suggesting etiologic roles for these traits in SCA risk.\n\nConclusionsOur findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in highrisk populations and the general community.

genetics↗