Blood co-expression modules identify potential modifier genes of diabetes and lung function in cystic fibrosis

A fibrose cística (FC) é uma doença genética rara que afeta os sistemas respiratório e digestivo. A doença pulmonar é variável entre pacientes com FC e está associada ao desenvolvimento de comorbidades e infecções crônicas. A taxa de deterioração da função pulmonar depende não apenas do tipo de mutações no CFTR, o gene causador da doença, mas também de genes modificadores. No presente estudo, objetivamos identificar genes e vias que (i) contribuem para a patogênese da fibrose cística e (ii) modulam as comorbidades associadas. Fizemos o perfil de amostras de sangue em pacientes com FC e controles saudáveis ​​e analisamos dados de RNA-seq com Weighted GeneCorrelation Network Analysis (WGCNA). Curiosamente, a função pulmonar, o índice de massa corporal, a presença de diabetes e infecções crônicas por P. aeruginosa se correlacionaram com quatro módulos de genes coexpressos. A inspeção detalhada de redes e genes centrais apontou para adesão celular, tráfego de leucócitos e produção de espécies reativas de oxigênio como mecanismos centrais no declínio da função pulmonar e diabetes relacionado à fibrose cística. Vale ressaltar que mostramos que o sangue é um tecido substituto informativo para estudar a contribuição da inflamação para a doença pulmonar e diabetes em pacientes com FC. Finalmente, fornecemos evidências de que o WGCNA é útil para analisar conjuntos de dados ômicos em doenças genéticas raras, pois as coortes de pacientes são inevitavelmente pequenas.Cystic fibrosis (CF) is a rare genetic disease that affects the respiratory and digestive systems. Lung disease is variable among CF patients and associated with the development of comorbidities and chronic infections. The rate of lung function deterioration depends not only on the type of mutations in CFTR, the disease-causing gene, but also on modifier genes. In the present study, we aimed to identify genes and pathways that (i) contribute to the pathogenesis of cystic fibrosis and (ii) modulate the associated comorbidities. We profiled blood samples in CF patients and healthy controls and analyzed RNA-seq data with Weighted GeneCorrelation Network Analysis (WGCNA). Interestingly, lung function, body massindex, the presence of diabetes, and chronic P. aeruginosa infections correlated with four modules of co-expressed genes. Detailed inspection of networks and hub genes pointed to cell adhesion, leukocyte trafficking and production of reactive oxygen species as central mechanisms in lung function decline and cystic fibrosis-related diabetes. Of note, we showed that blood is an informative surrogate tissue to study the contribution of inflammation to lung disease and diabetes in CF patients. Finally, we provided evidence that WGCNA is useful to analyze–omic datasets in rare genetic diseases as patient cohorts are inevitably small

Dynamic changes of DNA methylation and lung disease in cystic fibrosis: Lessons from a monogenic disease

Para avaliar se os níveis de metilação do DNA são responsáveis ​​pelas variações fenotípicas não hereditárias observadas entre pacientes com fibrose cística (FC). PACIENTES E MÉTODOS Usando o BeadChip de 450 K, nós perfilamos a metilação do DNA em células epiteliais nasais coletadas de 32 pacientes com FC e 16 controles. RESULTADOS Detectamos diferenças substanciais na metilação do DNA de até 55% (mudança β mediana de 0,13; IQR: 0,15-0,11) entre pacientes com FC e controles. Os níveis de metilação do DNA diferiram entre pacientes com FC leve e grave e se correlacionaram com a função pulmonar em 50 locais CpG. CONCLUSÃO Em amostras de FC, mudanças dinâmicas na metilação do DNA ocorreram em genes responsáveis ​​pela integridade do epitélio e pelas respostas inflamatórias e imunes, foram proeminentes em regiões genômicas transcricionalmente ativas e foram super-representadas em intensificadores ativos em tecidos pulmonares. ( Clinicaltrials.gov NCT02884622).To assess whether DNA methylation levels account for the noninherited phenotypic variations observed among cystic fibrosis (CF) patients. PATIENTS & METHODS Using the 450 K BeadChip, we profiled DNA methylation in nasal epithelial cells collected from 32 CF patients and 16 controls. RESULTS We detected substantial DNA methylation differences up to 55% (median β change 0.13; IQR: 0.15-0.11) between CF patients and controls. DNA methylation levels differed between mild and severe CF patients and correlated with lung function at 50 CpG sites. CONCLUSION In CF samples, dynamic changes of DNA methylation occurred in genes responsible for the integrity of the epithelium and the inflammatory and immune responses, were prominent in transcriptionally active genomic regions and were over-represented in enhancers active in lung tissues. ( Clinicaltrials.gov NCT02884622)

Physiological Responses of the Modified Shuttle Test in Adults With Cystic Fibrosis

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Use of the Peak Heart Rate Reached During Six-Minute Walk Test to Predict Individualized Training Intensity in Patients With Cystic Fibrosis: Validity and Reliability

International audienceUse of the peak heart rate reached during six-minute walk test to predict individualized training intensity in patients with cystic fibrosis: validity and reliability

L’endurance des muscles respiratoires dans la mucoviscidose : évaluation et impact clinique

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Deprescribing in older adults in a French community: a questionnaire study on patients’ beliefs and attitudes

International audienceBackground; General practitioners (GPs) have a central role to play on reduction of polypharmacy and deprescribing. This study aimed to assess beliefs and attitudes towards deprescribing in patients, aged 65 years or older in primary care, and to identify factors associated with deprescribing and their willingness to stop medication.Methods: A questionnaire study was performed between 23 May and 29 July 2022 on patients aged 65 years or older attending a GP’s surgery in a French area. We used the French version of the revised Patients’ Attitudes Towards Deprescribing self-report questionnaire (rPATD), which measures four subscales (“Burden”, “Appropriateness”, “Concerns about stopping” and, “Involvement”), patients’ willingness to stop one of their regular medicines, and patients’ satisfaction with their current medicines. Results The study enrolled 200 patients. Median age was 76 years old (IQR 71–81), 55% were women, and 42.5% took 5 or more medications per day. Although most patients (92.5%) were satisfied with their current medicines, 35% were reluctant to stop medications they had been taking for a long time, and 89.5% were willing to stop medication if asked to by their GP. Patients aged less than 75 years old reported more concerns about stopping. Women and patients with higher educational attainment showed significantly higher involvement in medication management. Conclusions The majority of older adults were willing to stop one or more of their regular medicines if asked to do so by their GP. GPs should address deprescribing into their current practice

Clinical practice versus guidelines for the screening of cystic fibrosis-related diabetes: A French survey from the 47 centers

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