21 research outputs found
Identification des gÚnes de susceptibilité à l'asthme à l'aide d'un criblage génomique par association en utilisant des pools d'ADN
Lâasthme est une maladie inflammatoire chronique des voies aĂ©riennes dont un pourcentage important sâexplique par des facteurs gĂ©nĂ©tiques. Les Ă©tudes en transcriptomique de lâasthme ont permis Ă ce jour dâidentifier plusieurs gĂšnes de susceptibilitĂ©. Notre revue de littĂ©rature a exposĂ© la disparitĂ© de telles Ă©tudes. NĂ©anmoins, ces Ă©tudes ont identifiĂ© des cibles thĂ©rapeutiques intĂ©ressantes qui permettront prochainement de mieux classifier et traiter les patients asthmatiques. Notre deuxiĂšme Ă©tude visait Ă identifier les loci associĂ©s Ă lâasthme Ă lâaide dâun criblage gĂ©nomique par association en utilisant des pools dâADN chez des femmes adultes canadiennes-françaises. Des criblages semblables ont dĂ©jĂ Ă©tĂ© effectuĂ©s par le passĂ© et nos rĂ©sultats confirment lâimplication des gĂšnes PTGDR et C3AR1 dans lâasthme. En Ă©tudiant un sous-groupe plus homogĂšne de patients asthmatiques, de nouvelles variations gĂ©nĂ©tiques ont Ă©tĂ© associĂ©es Ă lâasthme. Des analyses in silico et fonctionnelles, sur lâexpression des gĂšnes dans les poumons, ont complĂ©mentĂ© lâĂ©tude.Asthma is a chronic inflammatory disease of the airways which is largely explained by genetic factors. So far, transcriptomic studies of asthma have identified several susceptibility genes. Our review of the literature in this field has highlighted the disparity of such studies. However, those studies identified new therapeutic targets and biomarkers that are likely to improve asthma classification and treatments in a near future. Our second study aimed to identify loci associated with asthma using a pooling-based genome-wide association study in French Canadian adult women. Similar screens have been conducted in the past and our results confirmed the implication of C3AR1 and PTGDR in asthma. Using a more homogeneous subgroup of asthma patients, the study also revealed new genetic variants associated with asthma susceptibility. New findings were extended to gene expression in the lung and in silico analyzes
Deleterious variants in DCHS1 are prevalent in sporadic cases of mitral valve prolapse
Background: A recent study identified DCHS1 as a causal gene for mitral valve
prolapse. The goal of this study is to investigate the presence and frequency of
known and novel variants in this gene in 100 asymptomatic patients with moderate to severe organic mitral regurgitation.
Methods: DNA sequencing assays were developed for two previously identified
functional missense variants, namely p.R2330C and p.R2513H, and all 21 exons
of DCHS1. Pathogenicity of variants was evaluated in silico.
Results: p.R2330C and p.R2513H were not identified in this cohort. Sequencing
all coding regions revealed eight missense variants including six considered deleterious. This includes one novel variant (p.A2464P) and two rare variants
(p.R2770Q and p.R2462Q). These variants are predicted to be deleterious with
combined annotation-dependent depletion (CADD) scores greater than 25, which
are in the same range as p.R2330C (CADD = 28.0) and p.R2513H
(CADD = 24.3). More globally, 24 of 100 cases were carriers of at least one in
silico-predicted deleterious missense variant in DCHS1, suggesting that this single
gene may account for a substantial portion of cases.
Conclusion: This study reveals an important contribution of germline variants in
DCHS1 in unrelated patients with mitral valve prolapse and supports genetic testing of this gene to screen individuals at risk
Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank
Kim Valette et al. perform a genomic study on asthma integrating genome-wide association study, functional mapping using lung and blood transcriptome-wide profiles, as well as Mendelian randomization. They show candidate causal genes expressed in lung and blood tissues that are putative therapeutic targets for asthma
Role of BAFF in pulmonary autoantibody responses induced by chronic cigarette smoke exposure in mice
Emerging evidence suggests that autoimmune processes are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). In this study, we assessed the expression of B-cell activating factor (BAFF) in smokers, and investigated the functional importance of BAFF in the induction and maintenance of cigarette smoke-induced pulmonary antinuclear antibodies (ANA) and tertiary lymphoid tissues (TLTs) using a preclinical mouse model. We observed that BAFF levels were elevated in smokers and mice exposed to cigarette smoke. In mice, BAFF expression was rapidly induced in the lungs following 4 days of cigarette smoke exposure and remained elevated following 8 and 24 weeks of exposure. Alveolar macrophages were the major source of BAFF Blockade of BAFF using a BAFF receptor-Fc (BAFFR-Fc) construct prevented pulmonary ANA and TLT formation when delivered concurrent with cigarette smoke exposure. Under these conditions, no impact on lung inflammation was observed. However, administration of BAFFR-Fc following smoking cessation markedly reduced the number of TLTs and ANA levels and, of note, reduced pulmonary neutrophilia. Altogether, this study shows for the first time a central role of BAFF in the induction and maintenance of cigarette smoke-induced pulmonary ANA and suggests that BAFF blockade following smoking cessation could have beneficial effects on persistent inflammatory processes.In this study, we assessed the expression of B-cell activating factor (BAFF) in smokers, and investigated the functional importance of BAFF in the induction and maintenance of cigarette smoke-induced pulmonary antinuclear antibodies (ANA) and tertiary lymphoid tissues (TLTs) using a preclinical mouse model. Data presented show that BAFF plays a central role in the induction and maintenance of cigarette smoke-induced pulmonary ANA and suggest a therapeutic potential for BAFF blockade in limiting autoimmune processes associated with smoking
Linoleic acid supplementation of cell culture media influences the phospholipid and lipid profiles of human reconstructed adipose tissue.
Reconstructed human adipose tissues represent novel tools available to perform in vitro pharmaco-toxicological studies. We used adipose-derived human stromal/stem cells to reconstruct, using tissue engineering techniques, such an adipose tridimensional model. To determine to what extent the in vitro model is representative of its native counterpart, adipogenic differentiation, triglycerides accumulation and phospholipids profiles were analysed. Ingenuity Pathway Analysis software revealed pathways enriched with differentially-expressed genes between native and reconstructed human adipose tissues. Interestingly, genes related to fatty acid metabolism were downregulated in vitro, which could be explained in part by the insufficient amount of essential fatty acids provided by the fetal calf serum used for the culture. Indeed, the lipid profile of the reconstructed human adipose tissues indicated a particular lack of linoleic acid, which could interfere with physiological cell processes such as membrane trafficking, signaling and inflammatory responses. Supplementation in the culture medium was able to influence the lipid profile of the reconstructed human adipose tissues. This study demonstrates the possibility to directly modulate the phospholipid profile of reconstructed human adipose tissues. This reinforces its use as a relevant physiological or pathological model for further pharmacological and metabolic studies of human adipose tissue functions
Asthma susceptibility variants are more strongly associated with clinically similar subgroups
<p><i>Objective</i>: Genome-wide association studies (GWAS) identified single nucleotide polymorphisms (SNPs) reproducibly associated with asthma. This study evaluated whether GWAS-nominated SNPs are more strongly associated with asthma patients sharing the same clinical characteristics in order to refine the role of recently identified genes. <i>Methods</i>: Analyses were performed in unrelated French Canadian subjects (566 cases and 416 controls) with data collected on lung function, blood cell counts, atopy, disease history and medication. Previously defined asthma subgroups were used for analysis: 1) older patients with low atopy and low lung function, 2) high atopy, 3) young non-smoking women and 4) high smoking history. Allele frequencies of 68 GWAS-nominated SNPs were compared between controls and cases or controls and subgroups of cases defined by cluster analysis. <i>Results</i>: Twelve GWAS-nominated SNPs demonstrated evidence of replication (<i>p</i> value < 0.05) for association with asthma. In phenotypically similar asthma patients, rs10197862, located in <i>IL1RL1/IL18R1</i>, was the most strongly associated SNP with the high atopy subgroup (<i>p</i> = 0.0009). SNPs located at the <i>IL33</i> and the <i>STARD3</i>/<i>PGAP3</i> loci were also associated with the high atopy subgroup. Two SNPs, rs1544791 (<i>PDE4D</i>) and rs3806932 (<i>TSLP</i>), were more strongly associated with the high smoking history subgroup than with asthma or any other subgroups. All 10 SNPs that replicated for asthma <i>per se</i> and within subgroups had lower <i>p</i> values in subgroups. Moreover, 12 SNPs were only replicated in a subgroup. <i>Conclusion</i>: This study shows that the majority of GWAS-nominated SNPs are more strongly associated with homogeneous subgroups of asthma than broadly defined asthma.</p
Identification of susceptibility genes of adult asthma in french Canadian women
Susceptibility genes of asthma may be more successfully identified by studying subgroups of phenotypically similar asthma patients. This study aims to identify single nucleotide polymorphisms (SNPs) associated with asthma in French Canadian adult women. A pooling-based genome-wide association study was performed in 240 allergic asthmatic and 120 allergic nonasthmatic women. The top associated SNPs were selected for individual genotyping in an extended cohort of 349 asthmatic and 261 nonasthmatic women. The functional impact of asthma-associated SNPs was investigated in a lung expression quantitative trait loci (eQTL) mapping study (n = 1035). Twenty-one of the 38 SNPs tested by individual genotyping showed P values lower than 0.05 for association with asthma. Cis-eQTL analyses supported the functional contribution of rs17801353 associated with C3AR1 (P = 7.90E-10). The asthma risk allele for rs17801353 is associated with higher mRNA expression levels of C3AR1 in lung tissue. In silico functional characterization of the asthma-associated SNPs also supported the contribution of C3AR1 and additional genes including SYNE1, LINGO2, and IFNG-AS1. This pooling-based GWAS in French Canadian adult women followed by lung eQTL mapping suggested C3AR1 as a functional locus associated with asthma. Additional susceptibility genes were suggested in this homogenous subgroup of asthma patients