Publications by authors named "Yohan Bossé"

228 Publications

Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease.

Cell Rep Med 2021 Nov 3;2(11):100437. Epub 2021 Nov 3.

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada.

Non-alcoholic fatty liver disease (NAFLD) is a complex disease linked to several chronic diseases. We aimed at identifying genetic variants associated with NAFLD and evaluating their functional consequences. We performed a genome-wide meta-analysis of 4 cohorts of electronic health record-documented NAFLD in participants of European ancestry (8,434 cases and 770,180 controls). We identify 5 potential susceptibility loci for NAFLD (located at or near , , /, , and ). We also report a potentially causal effect of lower expression in adipose tissue on NAFLD susceptibility and an effect of the genotype on NAFLD. Positive genetic correlations between NAFLD and cardiometabolic diseases and risk factors such as body fat accumulation/distribution, lipoprotein-lipid levels, insulin resistance, and coronary artery disease and negative genetic correlations with parental lifespan, socio-economic status, and acetoacetate levels are observed. This large GWAS meta-analysis reveals insights into the genetic architecture of NAFLD.
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http://dx.doi.org/10.1016/j.xcrm.2021.100437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606899PMC
November 2021

A trans-omic Mendelian randomization study of parental lifespan uncovers novel aging biology and therapeutic candidates for chronic diseases.

Aging Cell 2021 11 27;20(11):e13497. Epub 2021 Oct 27.

Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada.

The study of parental lifespan has emerged as an innovative tool to advance aging biology and our understanding of the genetic architecture of human longevity and aging-associated diseases. Here, we leveraged summary statistics of a genome-wide association study including over one million parental lifespans to identify genetically regulated genes from the Genotype-Tissue Expression project. Through a combination of multi-tissue transcriptome-wide association analyses and genetic colocalization, we identified novel genes that may be associated with parental lifespan. Mendelian randomization (MR) analyses also identified circulating proteins and metabolites causally associated with parental lifespan and chronic diseases offering new drug repositioning opportunities such as those targeting apolipoprotein-B-containing lipoproteins. Liver expression of HP, the gene encoding haptoglobin, and plasma haptoglobin levels were causally linked with parental lifespan. Phenome-wide MR analyses were used to map genetically regulated genes, proteins and metabolites with other human traits as well as the disease-related phenome in the FinnGen cohorts (n = 135,638). Altogether, this study identified new candidate genes, circulating proteins and metabolites that may influence human aging as well as potential therapeutic targets for chronic diseases that warrant further investigation.
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http://dx.doi.org/10.1111/acel.13497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590095PMC
November 2021

Polygenic Risk Score for Coronary Artery Disease Improves the Prediction of Early-Onset Myocardial Infarction and Mortality in Men.

Circ Genom Precis Med 2021 Oct 21:CIRCGEN121003452. Epub 2021 Oct 21.

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Canada (H.D.M., A.E., N.P., Z.L., C.C., P.M., Y.B., B.J.A., S.T.).

Background: Several risk factors for coronary artery disease (CAD) have been described, some of which are genetically determined. The use of a polygenic risk score (PRS) could improve CAD risk assessment, but predictive accuracy according to age and sex is not well established.

Methods: A PRS including the weighted effects of >1.14 million SNPs associated with CAD was calculated in UK Biobank (n=408 422), using LDpred. Cox regressions were performed, stratified by age quartiles and sex, for incident myocardial infarction (MI) and mortality, with a median follow-up of 11.0 years. Improvement in risk prediction of MI was assessed by comparing PRS to the pooled cohort equation with categorical net reclassification index using a 2% threshold (NRI) and continuous NRI (NRI).

Results: From 7746 incident MI cases and 393 725 controls, hazard ratio for MI reached 1.53 (95% CI, 1.49-1.56; =2.69×10) per SD increase of PRS. PRS was significantly associated with MI in both sexes, with a stronger association in men (interaction =0.002), particularly in those aged between 40 and 51 years (hazard ratio, 2.00 [95% CI, 1.86-2.16], =1.93×10). This group showed the highest reclassification improvement, mainly driven by the up-classification of cases (NRI, 0.199 [95% CI, 0.157-0.248] and NRI, 0.602 [95% CI, 0.525-0.683]). From 23 982 deaths, hazard ratio for mortality was 1.08 (95% CI, 1.06-1.09; =5.46×10) per SD increase of PRS, with a stronger association in men (interaction =1.60×10).

Conclusions: Our PRS predicts MI incidence and all-cause mortality, especially in men aged between 40 and 51 years. PRS could optimize the identification and management of individuals at risk for CAD.
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http://dx.doi.org/10.1161/CIRCGEN.121.003452DOI Listing
October 2021

SARS-CoV-2 Impairs Dendritic Cells and Regulates DC-SIGN Gene Expression in Tissues.

Int J Mol Sci 2021 Aug 26;22(17). Epub 2021 Aug 26.

Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.

The current spreading coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three host receptors (ACE2, DC-SIGN and L-SIGN) of SARS coronaviruses and dendritic cells (DCs) status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of COVID-19 patients and healthy controls. In COVID-19 patients, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Within DCs, conventional DCs (cDCs) were depleted while plasmacytoid DCs (pDCs) were augmented in the lungs of mild COVID-19. In severe cases, we identified augmented types of immature DCs (CD22 or ANXA1 DCs) with MHCII downregulation. In this study, our observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically present SARS-CoV-2. It provides insights into the profound modulation of DC function in severe COVID-19.
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http://dx.doi.org/10.3390/ijms22179228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431536PMC
August 2021

Genomic and evolutionary classification of lung cancer in never smokers.

Nat Genet 2021 09 6;53(9):1348-1359. Epub 2021 Sep 6.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.
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http://dx.doi.org/10.1038/s41588-021-00920-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432745PMC
September 2021

IntraIndividual Variability in Serum Alpha-1 Antitrypsin Levels.

Chronic Obstr Pulm Dis 2021 Oct;8(4):464-473

Lakeshore General Hospital, Pointe-Claire, Québec, Canada.

Background: Measuring alpha-1 antitrypsin (AAT) serum levels is often the first step when investigating for alpha-1 antitrypsin deficiency (AATD). The purpose of this study was to determine the test-retest reproducibility of AAT serum levels and to determine if between-measurements variability was associated with acute phase markers of inflammation.

Methods: We retrospectively analyzed a sample of 255 patients from a community respirology practice with chronic obstructive pulmonary disease (COPD) in whom AAT serum levels were measured twice, on separate visits. White blood cell count and fibrinogen were also measured at the time of the second blood sampling as markers of acute phase inflammation. Intraclass correlation coefficient (ICC), Pearson correlation coefficient, and Bland-Altman analysis were used to document test-retest reproducibility. Regression analyses were used to identify potential correlates of test-retest AAT level differences.

Results: Although the 2 AAT serum levels were significantly correlated, the between-measurement agreement was weak (ICC of 0.38 [95% confidence interval (CI), 0.27 to 0.48]; Pearson correlation coefficient of 0.34 [95% CI, 0.23 to 0.44]) and Bland-Altman analysis revealed wide 95% limits of agreement. Considering that an AAT serum level below 1.13g/L should trigger further investigations to confirm the AAT status, discrepancies between the test-retest AAT levels resulted in reconsidering requirement for further investigation in 22% of patients. A significant correlation between the fibrinogen value and the second AAT level was found (=0.21, =0.004 [=173]).

Conclusions: Serum AAT levels showed weak intra-individual reproducibility which could lead to AATD status misclassification and potentially a missed diagnosis of AATD.
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http://dx.doi.org/10.15326/jcopdf.2021.0228DOI Listing
October 2021

ZNF768 links oncogenic RAS to cellular senescence.

Nat Commun 2021 08 17;12(1):4841. Epub 2021 Aug 17.

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval, Québec, QC, Canada.

RAS proteins are GTPases that lie upstream of a signaling network impacting cell fate determination. How cells integrate RAS activity to balance proliferation and cellular senescence is still incompletely characterized. Here, we identify ZNF768 as a phosphoprotein destabilized upon RAS activation. We report that ZNF768 depletion impairs proliferation and induces senescence by modulating the expression of key cell cycle effectors and established p53 targets. ZNF768 levels decrease in response to replicative-, stress- and oncogene-induced senescence. Interestingly, ZNF768 overexpression contributes to bypass RAS-induced senescence by repressing the p53 pathway. Furthermore, we show that ZNF768 interacts with and represses p53 phosphorylation and activity. Cancer genomics and immunohistochemical analyses reveal that ZNF768 is often amplified and/or overexpressed in tumors, suggesting that cells could use ZNF768 to bypass senescence, sustain proliferation and promote malignant transformation. Thus, we identify ZNF768 as a protein linking oncogenic signaling to the control of cell fate decision and proliferation.
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http://dx.doi.org/10.1038/s41467-021-24932-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370976PMC
August 2021

Lipoprotein Proteomics and Aortic Valve Transcriptomics Identify Biological Pathways Linking Lipoprotein(a) Levels to Aortic Stenosis.

Metabolites 2021 Jul 16;11(7). Epub 2021 Jul 16.

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC G1V 4G5, Canada.

Lipoprotein(a) (Lp(a)) is one of the most important risk factors for the development of calcific aortic valve stenosis (CAVS). However, the mechanisms through which Lp(a) causes CAVS are currently unknown. Our objectives were to characterize the Lp(a) proteome and to identify proteins that may be differentially associated with Lp(a) in patients with versus without CAVS. Our second objective was to identify genes that may be differentially regulated by exposure to high versus low Lp(a) levels in explanted aortic valves from patients with CAVS. We isolated Lp(a) from the blood of 21 patients with CAVS and 22 volunteers and performed untargeted label-free analysis of the Lp(a) proteome. We also investigated the transcriptomic signature of calcified aortic valves from patients who underwent aortic valve replacement with high versus low Lp(a) levels ( = 118). Proteins involved in the protein activation cascade, platelet degranulation, leukocyte migration, and response to wounding may be associated with Lp(a) depending on CAVS status. The transcriptomic analysis identified genes involved in cardiac aging, chondrocyte development, and inflammation as potentially influenced by Lp(a). Our multi-omic analyses identified biological pathways through which Lp(a) may cause CAVS, as well as key molecular events that could be triggered by Lp(a) in CAVS development.
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http://dx.doi.org/10.3390/metabo11070459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307014PMC
July 2021

Sex-Specific Associations of Genetically Predicted Circulating Lp(a) (Lipoprotein(a)) and Hepatic Gene Expression Levels With Cardiovascular Outcomes: Mendelian Randomization and Observational Analyses.

Circ Genom Precis Med 2021 08 19;14(4):e003271. Epub 2021 Jul 19.

Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (J.G., H.M., N.P., R.B., C.C., Y.B., P.P., P.M., M.-A.C., S.T., B.J.A.).

Background: Elevated Lp(a) (Lipoprotein(a)) levels are associated with coronary artery disease (CAD), ischemic stroke (IS), and calcific aortic valve stenosis (CAVS). Studies investigating the association between Lp(a) levels and these diseases in women have yielded inconsistent results.

Methods: To investigate the association of Lp(a) with sex-specific cardiovascular outcomes, we determined the association between genetically predicted Lp(a) levels (using 27 single nucleotide polymorphisms at the locus) and hepatic expression (using 80 single nucleotide polymorphisms at the locus associated with mRNA expression in liver samples from the Genotype-Tissue Expression dataset) on CAD, IS, and CAVS using individual participant data from the UK Biobank: 408 403 participants of European ancestry (37 102, 4283, and 2574 with prevalent CAD, IS, and CAVS, respectively). The long-term association between Lp(a) levels and incident CAD, IS, and CAVS was also investigated in European Prospective Investigation into Cancer and Nutrition-Norfolk: 18 721 participants (3964, 846, and 424 with incident CAD, IS, and CAVS, respectively).

Results: Genetically predicted plasma Lp(a) levels were positively and similarly associated with prevalent and incident CAD and CAVS in men and women. Genetically predicted plasma Lp(a) levels were associated with prevalent and incident IS when we studied men and women pooled together, and in men only. Genetically predicted expression levels were associated with prevalent CAD and CAVS in men and women but not with IS.

Conclusions: Genetically predicted blood Lp(a) and hepatic gene expression as well as serum Lp(a) levels predict the risk of CAD and CAVS in men and in women. Whether RNA interference therapies aiming at lowering Lp(a) levels could be useful in reducing cardiovascular disease risk in both men and women with high Lp(a) levels needs to be determined in large-scale cardiovascular outcomes trials.
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http://dx.doi.org/10.1161/CIRCGEN.120.003271DOI Listing
August 2021

Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank.

Commun Biol 2021 06 8;4(1):700. Epub 2021 Jun 8.

Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec, QC, Canada.

To identify candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS reveals 72 asthma-associated loci from 116 independent significant variants (P < 5.0E-8). The most significant lung TWAS gene on 17q12-q21 is GSDMB (P = 1.42E-54). Other TWAS genes include TSLP on 5q22, RERE on 1p36, CLEC16A on 16p13, and IL4R on 16p12, which all replicated in GTEx lung (n = 515). We demonstrate that the largest fold enrichment of regulatory and functional annotations among asthma-associated variants is in the blood. We map 485 blood eQTL-regulated genes associated with asthma and 50 of them are causal by Mendelian randomization. Prioritization of druggable genes reveals known (IL4R, TSLP, IL6, TNFSF4) and potentially new therapeutic targets for asthma.
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http://dx.doi.org/10.1038/s42003-021-02227-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187656PMC
June 2021

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

Enhancer-associated aortic valve stenosis risk locus 1p21.2 alters NFATC2 binding site and promotes fibrogenesis.

iScience 2021 Mar 27;24(3):102241. Epub 2021 Feb 27.

Laboratory of Cardiovascular Pathobiology, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, 2725 Chemin Ste-Foy, G1V-4G5, Québec City, QC, Canada.

Genome-wide association studies for calcific aortic valve stenosis (CAVS) previously reported strong signal for noncoding variants at 1p21.2. Previous study using Mendelian randomization suggested that the locus controls the expression of encoding Palmdelphin (PALMD). However, the molecular regulation at the locus and the impact of PALMD on the biology of the aortic valve is presently unknown. 3D genetic mapping and CRISPR activation identified rs6702619 as being located in a distant-acting enhancer, which controls the expression of . DNA-binding assay showed that the risk variant modified the DNA shape, which prevented the recruitment of NFATC2 and lowered the expression of . In co-expression network analysis, a module encompassing was enriched in actin-based process. Mass spectrometry and functional assessment showed that PALMD is a regulator of actin polymerization. In turn, lower level of PALMD promoted the activation of myocardin-related transcription factor and fibrosis, a key pathobiological process underpinning CAVS.
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http://dx.doi.org/10.1016/j.isci.2021.102241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970363PMC
March 2021

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

PLoS Genet 2021 03 5;17(3):e1009254. Epub 2021 Mar 5.

University of Salzburg, Department of Biosciences and Cancer Cluster Salzburg, Salzburg, Austria.

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.
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http://dx.doi.org/10.1371/journal.pgen.1009254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968735PMC
March 2021

System Genetics Including Causal Inference Identify Immune Targets for Coronary Artery Disease and the Lifespan.

Circ Genom Precis Med 2021 04 24;14(2):e003196. Epub 2021 Feb 24.

Laboratory of Cardiovascular Pathobiology, Quebec Heart and Lung Institute/Research Center, Department of Surgery (V.B.-B., A.C., M.-C.B., Z.L., D.A., P.M.), Laval University, Quebec, Canada.

Background: Randomized clinical trials indicate that the immune response plays a significant role in coronary artery disease (CAD), a disorder impacting the lifespan potential. However, the identification of targets critical to the immune response in atheroma is still hampered by a lack of solid inference.

Methods: Herein, we implemented a system genetics approach to identify causally associated immune targets implicated in atheroma. We leveraged genome-wide association studies to perform mapping and Mendelian randomization to assess causal associations between gene expression in blood cells with CAD and the lifespan. Expressed genes (eGenes) were prioritized in network and in single-cell expression derived from plaque immune cells.

Results: Among 840 CAD-associated blood eGenes, 37 were predicted causally associated with CAD and 6 were also associated with the parental lifespan in Mendelian randomization. In multivariable Mendelian randomization, the impact of eGenes on the lifespan potential was mediated by the CAD risk. Predicted causal eGenes were central in network. and were identified as targets of approved drugs, whereas 22 eGenes were deemed tractable for the development of small molecules and antibodies. Analyses of plaque immune single-cell expression identified predicted causal eGenes enriched in macrophages (, ) and involved in ligand-receptor interactions ().

Conclusions: We identified 37 blood eGenes predicted causally associated with CAD. The predicted expression for 6 eGenes impacted the lifespan potential through the risk of CAD. Prioritization based on network, annotations, and single-cell expression identified targets deemed tractable for the development of drugs and for drug repurposing.
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http://dx.doi.org/10.1161/CIRCGEN.120.003196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284374PMC
April 2021

Unravelling actionable biology using transcriptomic data to integrate mitotic index and Ki-67 in the management of lung neuroendocrine tumors.

Oncotarget 2021 Feb 2;12(3):209-220. Epub 2021 Feb 2.

Quebec Heart and Lung Institute Research Center, Quebec City, QC G1V4G5, Canada.

Pulmonary neuroendocrine tumors (NETs) are a heterogeneous family of malignancies whose classification relies on morphology and mitotic rate, unlike extrapulmonary neuroendocrine tumors that require both mitotic rate and Ki-67. As mitotic count is proportional to Ki-67, it is crucial to understand if Ki-67 can complement the existing diagnostic guidelines, as well as discover the benefit of these two markers to unravel the biological heterogeneity. In this study, we investigated the association of mitotic rate and Ki-67 at gene- and pathway-level using transcriptomic data in lung NET malignancies. Lung resection tumor specimens obtained from 28 patients diagnosed with NETs were selected. Mitotic rate, Ki-67 and transcriptomic data were obtained for all samples. The concordance between mitotic rate and Ki-67 was evaluated at gene-level and pathway-level using gene expression data. Our analysis revealed a strong association between mitotic rate and Ki-67 across all samples and cell cycle genes were found to be differentially ranked between them. Pathway analysis indicated that a greater number of pathways overlapped between these markers. Analyses based on lung NET subtypes revealed that mitotic rate in carcinoids and Ki-67 in large cell neuroendocrine carcinomas provided comprehensive characterization of pathways among these malignancies. Among the two subtypes, we found distinct leading-edge gene sets that drive the enrichment signal of commonly enriched pathways between mitotic index and Ki-67. Overall, our findings delineated the degree of benefit of the two proliferation markers, and offers new layer to predict the biological behavior and identify high-risk patients using a more comprehensive diagnostic workup.
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http://dx.doi.org/10.18632/oncotarget.27874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869577PMC
February 2021

Aryl hydrocarbon receptor deficiency causes the development of chronic obstructive pulmonary disease through the integration of multiple pathogenic mechanisms.

FASEB J 2021 03;35(3):e21376

Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Emphysema, a component of chronic obstructive pulmonary disease (COPD), is characterized by irreversible alveolar destruction that results in a progressive decline in lung function. This alveolar destruction is caused by cigarette smoke, the most important risk factor for COPD. Only 15%-20% of smokers develop COPD, suggesting that unknown factors contribute to disease pathogenesis. We postulate that the aryl hydrocarbon receptor (AHR), a receptor/transcription factor highly expressed in the lungs, may be a new susceptibility factor whose expression protects against COPD. Here, we report that Ahr-deficient mice chronically exposed to cigarette smoke develop airspace enlargement concomitant with a decline in lung function. Chronic cigarette smoke exposure also increased cleaved caspase-3, lowered SOD2 expression, and altered MMP9 and TIMP-1 levels in Ahr-deficient mice. We also show that people with COPD have reduced expression of pulmonary and systemic AHR, with systemic AHR mRNA levels positively correlating with lung function. Systemic AHR was also lower in never-smokers with COPD. Thus, AHR expression protects against the development of COPD by controlling interrelated mechanisms involved in the pathogenesis of this disease. This study identifies the AHR as a new, central player in the homeostatic maintenance of lung health, providing a foundation for the AHR as a novel therapeutic target and/or predictive biomarker in chronic lung disease.
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http://dx.doi.org/10.1096/fj.202002350RDOI Listing
March 2021

Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19.

Hum Genet 2021 Jun 19;140(6):969-979. Epub 2021 Feb 19.

Centre for Heart Lung Innovation, University of British Columbia, St. Paul's Hospital, Vancouver, BC, Canada.

SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain poorly understood. We, therefore, used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity. We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (n = 1,038) and eQTLGen (n = 31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (n = 3,301) with COVID-19 loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). The expression of 18 genes in lung and/or blood co-localized with COVID-19 loci. Of these, 12 genes were in suggestive loci (P < 5 × 10). LZTFL1, SLC6A20, ABO, IL10RB and IFNAR2 and OAS1 had been previously associated with a heightened risk of COVID-19 (P < 5 × 10). We identified a causal association between OAS1 and COVID-19 GWAS. Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in the MR analysis; increased plasma levels were associated with an increased risk of COVID-19 and, in particular, severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigations. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19.
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http://dx.doi.org/10.1007/s00439-021-02264-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892327PMC
June 2021

ACE inhibition and cardiometabolic risk factors, lung and gene expression, and plasma ACE2 levels: a Mendelian randomization study.

R Soc Open Sci 2020 Nov 18;7(11):200958. Epub 2020 Nov 18.

Computer Science Department and Center for Statistics and Machine Learning, Princeton University, Princeton, NJ, USA.

Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of and in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung and gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with gene expression in the Lung eQTL Consortium ( = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung gene expression in the Gene-Tissue Expression (GTEx) study ( = 4 × 10) and with circulating plasma ACE2 levels in the INTERVAL study ( = 0.03), but not with lung expression in the Lung eQTL Consortium study ( = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung and expression or plasma ACE2 levels.
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http://dx.doi.org/10.1098/rsos.200958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735342PMC
November 2020

Gene expression network analysis provides potential targets against SARS-CoV-2.

Sci Rep 2020 12 14;10(1):21863. Epub 2020 Dec 14.

Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada.

Cell entry of SARS-CoV-2, the novel coronavirus causing COVID-19, is facilitated by host cell angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We aimed to identify and characterize genes that are co-expressed with ACE2 and TMPRSS2, and to further explore their biological functions and potential as druggable targets. Using the gene expression profiles of 1,038 lung tissue samples, we performed a weighted gene correlation network analysis (WGCNA) to identify modules of co-expressed genes. We explored the biology of co-expressed genes using bioinformatics databases, and identified known drug-gene interactions. ACE2 was in a module of 681 co-expressed genes; 10 genes with moderate-high correlation with ACE2 (r > 0.3, FDR < 0.05) had known interactions with existing drug compounds. TMPRSS2 was in a module of 1,086 co-expressed genes; 31 of these genes were enriched in the gene ontology biologic process 'receptor-mediated endocytosis', and 52 TMPRSS2-correlated genes had known interactions with drug compounds. Dozens of genes are co-expressed with ACE2 and TMPRSS2, many of which have plausible links to COVID-19 pathophysiology. Many of the co-expressed genes are potentially targetable with existing drugs, which may accelerate the development of COVID-19 therapeutics.
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http://dx.doi.org/10.1038/s41598-020-78818-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736291PMC
December 2020

Oxyphospholipids in Cardiovascular Calcification.

Arterioscler Thromb Vasc Biol 2021 01 24;41(1):11-19. Epub 2020 Nov 24.

Department of Surgery, Laboratory of Cardiovascular Pathobiology, Quebec Heart and Lung Institute/Research Center (A.C., V.B.-B., M.-C.B., P.M.), Laval University, Canada.

Mineralization of cardiovascular structures including blood vessels and heart valves is a common feature. We postulate that ectopic mineralization is a response-to-injury in which signals delivered to cells trigger a chain of events to restore and repair tissues. Maladaptive response to external or internal signals promote the expression of danger-associated molecular patterns, which, in turn, promote, when expressed chronically, a procalcifying gene program. Growing evidence suggest that danger-associated molecular patterns such as oxyphospholipids and small lipid mediators, generated by enzyme activity, are involved in the transition of vascular smooth muscle cells and valve interstitial cells to an osteoblast-like phenotype. Understanding the regulation and the molecular processes underpinning the mineralization of atherosclerotic plaques and cardiac valves are providing valuable mechanistic insights, which could lead to the development of novel therapies. Herein, we provide a focus account on the role oxyphospholipids and their mediators in the development of mineralization in plaques and calcific aortic valve disease.
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http://dx.doi.org/10.1161/ATVBAHA.120.313790DOI Listing
January 2021

The Clinical Utility of Determining the Allelic Background of Mutations Causing Alpha-1 Antitrypsin Deficiency: The Case with the Null Variant Q0(Mattawa)/Q0(Ourém).

Chronic Obstr Pulm Dis 2021 Jan;8(1)

Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval, Québec, QC, Canada.

Background: Alpha-1 antitrypsin deficiency (AATD) is caused by genetic variants in the gene conferring risk of developing emphysema. The clinical expression of AATD-related emphysema mostly occurs in carriers of 2 deficient alleles. By DNA sequencing of , numerous rare variants have been identified. Clarifying whether 2 mutations observed in 1 patient are on the same or distinct alleles has obvious clinical implications.

Methods: We studied 7 carriers of a rare variant, Leu353Phe_fsTer24, known to lead to undetectable serum levels of AAT. Two of them were also carriers of the S or Z allele. We developed an allele-specific DNA sequencing method to characterize the allelic background of the Leu353Phe_fsTer24 variant.

Results: The Leu353Phe_fsTer24 variant was transmitted on the same allele as the M3 variant (E376D) in all patients. This mutation is thus named Q0 on the conventional PI system. We demonstrated that individuals harboring the E264V (S) and E342K (Z) mutations had them on distinct alleles from Q0 and are, thus, compound heterozygotes. The 7 Q0 carriers had AAT levels ranging from 0.18g/l to 0.82g/l. The lowest AAT serum levels were observed in compound heterozygotes (S/Q0 and Z/Q0) suggesting higher risk of developing emphysema.

Conclusion: For the 7 patients, Leu353Phe_fsTer24 is transmitted on the M3 background and they are, thus, carriers of the Q0 allele. Allele-specific DNA sequencing was useful to distinguish 1 or 2 deficient alleles in carriers of 2 mutations. In rare cases, this method is important to understand the clinical significance of genetic variants found in .
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http://dx.doi.org/10.15326/jcopdf.8.1.2020.0168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047621PMC
January 2021

The landscape of host genetic factors involved in immune response to common viral infections.

Genome Med 2020 10 27;12(1):93. Epub 2020 Oct 27.

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.

Background: Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities.

Methods: We conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort.

Results: Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRβ1 at positions 11, 13, 71, and 74 for Epstein-Barr virus (EBV), Varicella zoster virus (VZV), human herpesvirus 7, (HHV7), and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response (P < 5.0 × 10), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, and CXCR5 (11q23.3) and TBKBP1 (17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P = 5.0 × 10 (MCV), NTN5: P = 1.1 × 10 (BKV), and P2RY13: P = 1.1 × 10 EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases, from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions.

Conclusions: Our study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.
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http://dx.doi.org/10.1186/s13073-020-00790-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590248PMC
October 2020

Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer.

Genet Epidemiol 2021 02 14;45(1):99-114. Epub 2020 Sep 14.

Faculty of Medical Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1β pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.
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http://dx.doi.org/10.1002/gepi.22358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855632PMC
February 2021

Phenome-wide analyses establish a specific association between aortic valve PALMD expression and calcific aortic valve stenosis.

Commun Biol 2020 08 28;3(1):477. Epub 2020 Aug 28.

Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval, Quebec City, QC, G1V 0A6, Canada.

Calcific aortic valve stenosis (CAVS) is a frequent heart disease with significant morbidity and mortality. Recent genomic studies have identified a locus near the gene PALMD (palmdelphin) strongly associated with CAVS. Here, we show that genetically-determined expression of PALMD in the aortic valve is inversely associated with CAVS, with a stronger effect in women, in a meta-analysis of two large cohorts totaling 2359 cases and 350,060 controls. We further demonstrate the specificity of this relationship by showing the absence of other significant association between the genetically-determined expression of PALMD in 9 tissues and 852 phenotypes. Using genome-wide association studies meta-analyses of cardiovascular traits, we identify a significant colocalized positive association between genetically-determined expression of PALMD in four non-cardiac tissues (brain anterior cingulate cortex, esophagus muscularis, tibial nerve and subcutaneous adipose tissue) and atrial fibrillation. The present work further establishes PALMD as a promising molecular target for CAVS.
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http://dx.doi.org/10.1038/s42003-020-01210-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455695PMC
August 2020

Protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study.

Thorax 2020 11 24;75(11):934-943. Epub 2020 Aug 24.

Centre for Heart Lung Innovation, St Paul's Hospital, The University of British Columbia, Vancouver, British Columbia, Canada.

Background: The anti-inflammatory pneumoprotein club cell secretory protein-16 (CC-16) is associated with the clinical expression of chronic obstructive pulmonary disease (COPD). We aimed to determine if there is a causal effect of serum CC-16 level on the risk of having COPD and/or its progression using Mendelian randomisation (MR) analysis.

Methods: We performed a genome-wide association meta-analysis for serum CC-16 in two COPD cohorts (Lung Health Study (LHS), n=3850 and ECLIPSE, n=1702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) as instrumental variables in MR analysis to identify a causal effect of serum CC-16 on 'COPD risk' (ie, case status in the International COPD Genetics Consortium/UK-Biobank dataset; n=35 735 COPD cases, n=222 076 controls) and 'COPD progression' (ie, annual change in forced expiratory volume in 1 s in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1111 lung tissue samples from the Lung Expression Quantitative Trait Locus Study.

Results: We identified seven SNPs independently associated (p<5×10) with serum CC-16 levels; six of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (MR estimate (SE) -0.11 (0.04), p=0.008) and progression (LHS only, MR estimate (SE) 7.40 (3.28), p=0.02). Five of the SNPs were also associated with gene expression in lung tissue (at false discovery rate <0.1) of several genes, including the CC-16-encoding gene .

Conclusion: We have identified several novel genetic variants associated with serum CC-16 level in COPD cohorts. These genetic associations suggest a potential causal effect of serum CC-16 on the risk of having COPD and its progression, the biological basis of which warrants further investigation.
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http://dx.doi.org/10.1136/thoraxjnl-2019-214487DOI Listing
November 2020

Genetic and In Vitro Inhibition of and Calcific Aortic Valve Stenosis.

JACC Basic Transl Sci 2020 Jul 1;5(7):649-661. Epub 2020 Jul 1.

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada.

The authors investigated whether PCSK9 inhibition could represent a therapeutic strategy in calcific aortic valve stenosis (CAVS). A meta-analysis of 10 studies was performed to determine the impact of the R46L variant on CAVS, and the authors found that CAVS was less prevalent in carriers of this variant (odds ratio: 0.80 [95% confidence interval: 0.70 to 0.91]; p = 0.0011) compared with noncarriers. PCSK9 expression was higher in the aortic valves of patients CAVS compared with control patients. In human valve interstitials cells submitted to a pro-osteogenic medium, PCSK9 levels increased and a PCSK9 neutralizing antibody significantly reduced calcium accumulation.
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http://dx.doi.org/10.1016/j.jacbts.2020.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393433PMC
July 2020

Genetic Determinants of Lung Cancer Prognosis in Never Smokers: A Pooled Analysis in the International Lung Cancer Consortium.

Cancer Epidemiol Biomarkers Prev 2020 10 22;29(10):1983-1992. Epub 2020 Jul 22.

Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.

Background: Lung cancer remains the leading cause of cancer death worldwide, with 15% to 20% occurring in never smokers. To assess genetic determinants for prognosis among never smokers, we conducted a genome-wide investigation in the International Lung Cancer Consortium (ILCCO).

Methods: Genomic and clinical data from 1,569 never-smoking patients with lung cancer of European ancestry from 10 ILCCO studies were included. HRs and 95% confidence intervals of overall survival were estimated. We assessed whether the associations were mediated through mRNA expression-based 1,553 normal lung tissues from the lung expression quantitative trait loci (eQTL) dataset and Genotype-Tissue Expression (GTEx). For cross-ethnicity generalization, we assessed the associations in a Japanese study ( = 887).

Results: One locus at 13q22.2 was associated with lung adenocarcinoma survival at genome-wide level, with carriers of rs12875562-T allele exhibiting poor prognosis [HR = 1.71 (1.41-2.07), = 3.60 × 10], and altered mRNA expression of in lung tissue (GTEx, = 9.40 × 10; Lung eQTL dataset, = 0.003). Furthermore, 2 of 11 independent loci that reached the suggestive significance level ( < 10) were significant eQTL affecting mRNA expression of nearby genes in lung tissues, including at 1p36.13 and at 9q34.3. One locus encoding at 4p14 showed associations in both European [HR = 0.50 (0.38-0.66), = 6.92 × 10] and Japanese populations [HR = 0.79 (0.67-0.94), = 0.007].

Conclusions: Based on the largest genomic investigation on the lung cancer prognosis of never smokers to date, we observed that lung cancer prognosis is affected by inherited genetic variants.

Impact: We identified one locus near at genome-wide level and several potential prognostic genes with -effect on mRNA expression. Further functional genomics work is required to understand their role in tumor progression.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541720PMC
October 2020

Lipoprotein-associated phospholipase A2 activity, genetics and calcific aortic valve stenosis in humans.

Heart 2020 09 7;106(18):1407-1412. Epub 2020 Jul 7.

Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec city, Québec, Canada

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been shown to predict calcific aortic valve stenosis (CAVS) outcomes. Our objective was to test the association between plasma Lp-PLA2 activity and genetically elevated Lp-PLA2 mass/activity with CAVS in humans.

Methods And Results: Lp-PLA2 activity was measured in 890 patients undergoing cardiac surgery, including 476 patients undergoing aortic valve replacement for CAVS and 414 control patients undergoing coronary artery bypass grafting. After multivariable adjustment, Lp-PLA2 activity was positively associated with the presence of CAVS (OR=1.21 (95% CI 1.04 to 1.41) per SD increment). We selected four single nucleotide polymorphisms (SNPs) at the locus associated with either Lp-PLA2 mass or activity (rs7756935, rs1421368, rs1805017 and rs4498351). Genetic association studies were performed in eight cohorts: Quebec-CAVS (1009 cases/1017 controls), UK Biobank (1350 cases/349 043 controls), European Prospective Investigation into Cancer and Nutrition-Norfolk (504 cases/20 307 controls), Genetic Epidemiology Research on Aging (3469 cases/51 723 controls), Malmö Diet and Cancer Study (682 cases/5963 controls) and three French cohorts (3123 cases/6532 controls), totalling 10 137 CAVS cases and 434 585 controls. A fixed-effect meta-analysis using the inverse-variance weighted method revealed that none of the four SNPs was associated with CAVS (OR=0.99 (95% CI 0.96 to 1.02, p=0.55) for rs7756935, 0.97 (95% CI 0.93 to 1.01, p=0.11) for rs1421368, 1.00 (95% CI 1.00 to 1.01, p=0.29) for rs1805017, and 1.00 (95% CI 0.97 to 1.04, p=0.87) for rs4498351).

Conclusions: Higher Lp-PLA2 activity is significantly associated with the presence of CAVS and might represent a biomarker of CAVS in patients with heart disease. Results of our genetic association study suggest that Lp-PLA2 is however unlikely to represent a causal risk factor or therapeutic target for CAVS.
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http://dx.doi.org/10.1136/heartjnl-2020-316722DOI Listing
September 2020

The landscape of host genetic factors involved in immune response to common viral infections.

medRxiv 2020 Sep 5. Epub 2020 Sep 5.

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA.

Introduction: Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities.

Methods: We conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort.

Results: Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRβ1 at positions 11, 13, 71, and 74 for Epstein-Barr Virus (EBV), Varicella Zoster Virus (VZV), Human Herpes virus 7, (HHV7) and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response (<5.×10), including (19q13.33) for human polyomavirus BK (BKV), (5q31.2) for MCV, as well as (11q23.3) and (17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including : =5.0×10 (MCV), : =1.1×10 (BKV), and : =1.1×10 EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases; from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions.

Conclusions: Our study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.
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http://dx.doi.org/10.1101/2020.05.01.20088054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273301PMC
September 2020
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