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Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10−44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

Purpose Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator ( CFTR ), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis–related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. Methods Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n  = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n  = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. Results The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1 , which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. Conclusion We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

Le but du projet était de comparer la toxicité de trois types de nanoparticules (NPs) et d'évaluer si ces NPs pouvaient influencer la réponse des lymphocytes T à l'interleukine 2 (IL-2). Pour ce faire, nous avons utilisé une lignée de cellules T CD4 lymphoblastoïde IL-2-dépendante, la lignée WE17/10. Les trois types de NPs utilisés étaient celles d'argent (Ag), de fullerène (C60) et de ferrite de zinc (ZnFe2O4). Parmi les trois, seulement les NPs d'Ag étaient cytotoxiques à la concentration testée la plus élevée. La caractérisation a permis de déterminer que les NPs de C60 et ZnFe2O4 formaient de gros agrégats, alors que celles d'Ag étaient relativement bien dispersées et plus stables. Cela se traduisait par une entrée plus importante des NPs d'Ag à l'intérieur des cellules, tel qu'évalué par cytométrie en flux en mesurant le changement de granularité en fonction de la concentration de NPs. La mesure de la prolifération cellulaire a montré que les NPs d'Ag avaient davantage d'effet en réduisant considérablement la prolifération à des concentrations n'affectant pas la viabilité cellulaire. Les NPs de C60 et ZnFe2O4 augmentaient légèrement la prolifération. Certaines protéines impliquées dans les voies de signalisation déclenchées par le récepteur à l'IL-2 furent analysées. Aucun effet significatif ne fut mesuré au niveau de l'activation du facteur de transcription Stat5 et des MAPK ERKI/2 et JNK, à l'exception de ERKl/2 à la suite d'une courte exposition aux NPs d'Ag. Une analyse plus approfondie fut effectuée par réseaux d'anticorps à la suite de l'exposition aux NPs de ZnFe2O4. Cela a permis d'identifier plusieurs tyrosine kinases dont le niveau d'activation était modifié. La phosphorylation des protéines Fer et ABLl étaient notamment fortement augmentée, deux protéines connues pour être activées à la suite d'un stress cellulaire et pouvant stimuler la prolifération. Une étude plus approfondie sera nécessaire pour établir par quel mécanisme ces NPs agissent. Les résultats que nous avons obtenus montrent que les NPs d'Ag présentent une toxicité plus grande, mais ne permettent pas d'établir si les NPs étudiées interfèrent ou non dans la réponse des lymphocytes T CD4 à l'IL-2.

Phasing of heterozygous alleles is critical for interpretation of cis-effects of disease-relevant variation. For population studies, phase is often inferred from external data but read-based phasing approaches that span long genomic distances would be more accurate because they enable both genotype and phase to be obtained from a single dataset. To demonstrate how read-based phasing can provide functional insights, we sequenced 477 individuals with Cystic Fibrosis (CF) using linked-read sequencing. We benchmark read-based phasing with different short- and long-read sequencing technologies, prioritize linked-read technology as the most informative and produce a benchmark phase call set from reference sample HG002 for the community. The 477 samples display an average phase block N50 of 4.39 Mb. We use these samples to construct a graph representation of CFTR haplotypes, which facilitates understanding of complex CF alleles. Fine-mapping and phasing of the chr7q35 trypsinogen locus associated with CF meconium ileus demonstrates a 20 kb deletion and a PRSS2 missense variant p.Thr8Ile (rs62473563) independently contribute to meconium ileus risk (p=0.0028, p=0.011, respectively) and are PRSS2 pancreas eQTLs (p=9.5e-7 and p=1.4e-4, respectively), explaining the mechanism by which these polymorphisms contribute to CF. Phase enables access to haplotypes that can be used for genome graph or reference panel construction, identification of cis-effects, and for understanding disease associated loci. The phase information from linked-reads provides a causal explanation for variation at a CF-relevant locus which also has implications for the genetic basis of non-CF pancreatitis to which this locus has been reported to contribute. Competing Interest Statement DMC received an honorarium for teaching module development for Vertex Pharmaceuticals. NM is doing contract research trials for Vertex Phaemaceuticals and Abbvie. ALS has received speaking fees for educational programs sponsored by Vertex Pharmaceuticals. BSQ has received speaker fees from Vertex Pharmaceuticals and has served as site PI for several Vertex-sponsored clinical trials. WML is a study investigator for Vertex Pharmaceuticals. ET and FR act as consultants for Vertex Pharmaceuticals. MS participated in Vertex clinical trials and received payment for education modules. SM, AC, JG, FL, BT, WWLS, JW, ZW, RVP, KK, AH, NP, JA, CW, GCM, SB, DA, EB, CB, MC, AP, MP, RVW, DH, MJS, ET, PW, LS, FR, and LJS have no conflicts of interest.