Umeå University's logo

umu.sePublications
Change search
Link to record
Permanent link

Direct link
Behndig, Annelie F.
Alternative names
Publications (10 of 73) Show all publications
Wang, X., Zhang, Z., Ding, Y., Chen, T., Mucci, L., Albanes, D., . . . Christiani, D. C. (2024). Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification. Genome Medicine, 16(1), Article ID 22.
Open this publication in new window or tab >>Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification
Show others...
2024 (English)In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 16, no 1, article id 22Article in journal (Refereed) Published
Abstract [en]

Background: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored.

Methods: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold.

Results: Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12–3.50, P-value = 4.13 × 10−15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99–2.49, P-value = 5.70 × 10−46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72–0.74). Conclusions: Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024
Keywords
Cancer control, Genetic epidemiology, Non-small cell lung cancer (NSCLC), Polygenic risk score (PRSs), Population science
National Category
Medical Genetics Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-221118 (URN)10.1186/s13073-024-01298-4 (DOI)001159054600004 ()38317189 (PubMedID)2-s2.0-85184421171 (Scopus ID)
Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-27Bibliographically approved
Midttun, Ø., Ulvik, A., Meyer, K., Zahed, H., Giles, G. G., Manjer, J., . . . Ueland, P. M. (2023). A cross-sectional study of inflammatory markers as determinants of circulating kynurenines in the Lung Cancer Cohort Consortium. Scientific Reports, 13(1), Article ID 1011.
Open this publication in new window or tab >>A cross-sectional study of inflammatory markers as determinants of circulating kynurenines in the Lung Cancer Cohort Consortium
Show others...
2023 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, no 1, article id 1011Article in journal (Refereed) Published
Abstract [en]

Circulating concentrations of metabolites (collectively called kynurenines) in the kynurenine pathway of tryptophan metabolism increase during inflammation, particularly in response to interferon-gamma (IFN-γ). Neopterin and the kynurenine/tryptophan ratio (KTR) are IFN-γ induced inflammatory markers, and together with C-reactive protein (CRP) and kynurenines they are associated with various diseases, but comprehensive data on the strength of associations of inflammatory markers with circulating concentrations of kynurenines are lacking. We measured circulating concentrations of neopterin, CRP, tryptophan and seven kynurenines in 5314 controls from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). The associations of neopterin, KTR and CRP with kynurenines were investigated using regression models. In mixed models, one standard deviation (SD) higher KTR was associated with a 0.46 SD higher quinolinic acid (QA), and 0.31 SD higher 3-hydroxykynurenine (HK). One SD higher neopterin was associated with 0.48, 0.44, 0.36 and 0.28 SD higher KTR, QA, kynurenine and HK, respectively. KTR and neopterin respectively explained 24.1% and 16.7% of the variation in QA, and 11.4% and 7.5% of HK. CRP was only weakly associated with kynurenines in regression models. In summary, QA was the metabolite that was most strongly associated with the inflammatory markers. In general, the inflammatory markers were most strongly related to metabolites located along the tryptophan-NAD axis, which may support suggestions of increased production of NAD from tryptophan during inflammation.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-204156 (URN)10.1038/s41598-023-28135-9 (DOI)001003289000030 ()36653422 (PubMedID)2-s2.0-85146485674 (Scopus ID)
Available from: 2023-01-30 Created: 2023-01-30 Last updated: 2023-09-05Bibliographically approved
Friberg, M., Behndig, A. F., Bosson, J., Muala, A., Barath, S., Dove, R., . . . Pourazar, J. (2023). Human exposure to diesel exhaust induces CYP1A1 expression and AhR activation without a coordinated antioxidant response. Particle and Fibre Toxicology, 20(1), Article ID 47.
Open this publication in new window or tab >>Human exposure to diesel exhaust induces CYP1A1 expression and AhR activation without a coordinated antioxidant response
Show others...
2023 (English)In: Particle and Fibre Toxicology, E-ISSN 1743-8977, Vol. 20, no 1, article id 47Article in journal (Refereed) Published
Abstract [en]

Background: Diesel exhaust (DE) induces neutrophilia and lymphocytosis in experimentally exposed humans. These responses occur in parallel to nuclear migration of NF-κB and c-Jun, activation of mitogen activated protein kinases and increased production of inflammatory mediators. There remains uncertainty regarding the impact of DE on endogenous antioxidant and xenobiotic defences, mediated by nuclear factor erythroid 2-related factor 2 (Nrf2) and the aryl hydrocarbon receptor (AhR) respectively, and the extent to which cellular antioxidant adaptations protect against the adverse effects of DE.

Methods: Using immunohistochemistry we investigated the nuclear localization of Nrf2 and AhR in the epithelium of endobronchial mucosal biopsies from healthy subjects six-hours post exposure to DE (PM10, 300 µg/m3) versus post-filtered air in a randomized double blind study, as a marker of activation. Cytoplasmic expression of cytochrome P450s, family 1, subfamily A, polypeptide 1 (CYP1A1) and subfamily B, Polypeptide 1 (CYP1B1) were examined to confirm AhR activation; with the expression of aldo–keto reductases (AKR1A1, AKR1C1 and AKR1C3), epoxide hydrolase and NAD(P)H dehydrogenase quinone 1 (NQO1) also quantified. Inflammatory and oxidative stress markers were examined to contextualize the responses observed.

Results: DE exposure caused an influx of neutrophils to the bronchial airway surface (p = 0.013), as well as increased bronchial submucosal neutrophil (p < 0.001), lymphocyte (p = 0.007) and mast cell (p = 0.002) numbers. In addition, DE exposure enhanced the nuclear translocation of the AhR and increased the CYP1A1 expression in the bronchial epithelium (p = 0.001 and p = 0.028, respectively). Nuclear translocation of AhR was also increased in the submucosal leukocytes (p < 0.001). Epithelial nuclear AhR expression was negatively associated with bronchial submucosal CD3 numbers post DE (r = −0.706, p = 0.002). In contrast, DE did not increase nuclear translocation of Nrf2 and was associated with decreased NQO1 in bronchial epithelial cells (p = 0.02), without affecting CYP1B1, aldo–keto reductases, or epoxide hydrolase protein expression.

Conclusion: These in vivo human data confirm earlier cell and animal-based observations of the induction of the AhR and CYP1A1 by diesel exhaust. The induction of phase I xenobiotic response occurred in the absence of the induction of antioxidant or phase II xenobiotic defences at the investigated time point 6 h post-exposures. This suggests DE-associated compounds, such as polycyclic aromatic hydrocarbons (PAHs), may induce acute inflammation and alter detoxification enzymes without concomitant protective cellular adaptations in human airways.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Aryl hydrocarbon receptor, Diesel exhaust, Immunohistochemistry, Oxidative stress, Xenobiotic metabolism
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-218128 (URN)10.1186/s12989-023-00559-1 (DOI)38062420 (PubMedID)2-s2.0-85178874563 (Scopus ID)
Funder
Västerbotten County CouncilSwedish Heart Lung FoundationUmeå University
Available from: 2023-12-15 Created: 2023-12-15 Last updated: 2023-12-15Bibliographically approved
Yasinska, V., Gómez, C., Kolmert, J., Ericsson, M., Pohanka, A., James, A., . . . Jonsson, E. W. (2023). Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids. ERJ Open Research, 9(5), Article ID 00269-2023.
Open this publication in new window or tab >>Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids
Show others...
2023 (English)In: ERJ Open Research, E-ISSN 2312-0541, Vol. 9, no 5, article id 00269-2023Article in journal (Refereed) Published
Abstract [en]

Rationale: Patients with severe asthma are dependent upon treatment with high doses of inhaled corticosteroids (ICS) and often also oral corticosteroids (OCS). The extent of endogenous androgenic anabolic steroid (EAAS) suppression in asthma has not previously been described in detail. The objective of the present study was to measure urinary concentrations of EAAS in relation to exogenous corticosteroid exposure.

Methods: Urine collected at baseline in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcomes) study of severe adult asthmatics (SA, n=408) was analysed by quantitative mass spectrometry. Data were compared to that of mild-to-moderate asthmatics (MMA, n=70) and healthy subjects (HC, n=98) from the same study.

Measurements and main results: The concentrations of urinary endogenous steroid metabolites were substantially lower in SA than in MMA or HC. These differences were more pronounced in SA patients with detectable urinary OCS metabolites. Their dehydroepiandrosterone sulfate (DHEA-S) concentrations were <5% of those in HC, and cortisol concentrations were below the detection limit in 75% of females and 82% of males. The concentrations of EAAS in OCS-positive patients, as well as patients on high-dose ICS only, were more suppressed in females than males (p<0.05). Low levels of DHEA were associated with features of more severe disease and were more prevalent in females (p<0.05). The association between low EAAS and corticosteroid treatment was replicated in 289 of the SA patients at follow-up after 12–18 months.

Conclusion: The pronounced suppression of endogenous anabolic androgens in females might contribute to sex differences regarding the prevalence of severe asthma.

Place, publisher, year, edition, pages
European Respiratory Society, 2023
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-215705 (URN)10.1183/23120541.00269-2023 (DOI)001075451800015 ()37868143 (PubMedID)2-s2.0-85173750900 (Scopus ID)
Funder
Swedish Heart Lung Foundation, HLF 20210519Swedish Research CouncilEU, FP7, Seventh Framework ProgrammeConsul Berghs FoundationKarolinska InstituteVårdal Foundation
Available from: 2023-11-13 Created: 2023-11-13 Last updated: 2023-11-13Bibliographically approved
Hansson, A., Rankin, G., Uski, O., Sehlstedt, M., Pourazar, J., Lindgren, R., . . . Muala, A. (2023). Reduced bronchoalveolar macrophage phagocytosis and cytotoxic effects after controlled short-term exposure to wood smoke in healthy humans. Particle and Fibre Toxicology, 20(1), Article ID 30.
Open this publication in new window or tab >>Reduced bronchoalveolar macrophage phagocytosis and cytotoxic effects after controlled short-term exposure to wood smoke in healthy humans
Show others...
2023 (English)In: Particle and Fibre Toxicology, E-ISSN 1743-8977, Vol. 20, no 1, article id 30Article in journal (Refereed) Published
Abstract [en]

Background: Exposure to wood smoke has been shown to contribute to adverse respiratory health effects including airway infections, but the underlying mechanisms are unclear. A preceding study failed to confirm any acute inflammation or cell influx in bronchial wash (BW) or bronchoalveolar lavage (BAL) 24 h after wood smoke exposure but showed unexpected reductions in leukocyte numbers. The present study was performed to investigate responses at an earlier phase, regarding potential development of acute inflammation, as well as indications of cytotoxicity.

Methods: In a double-blind, randomised crossover study, 14 healthy participants were exposed for 2 h to filtered air and diluted wood smoke from incomplete wood log combustion in a common wood stove with a mean particulate matter concentration of 409 µg/m3. Bronchoscopy with BW and BAL was performed 6 h after exposure. Differential cell counts, assessment of DNA-damage and ex vivo analysis of phagocytic function of phagocytosing BAL cells were performed. Wood smoke particles were also collected for in vitro toxicological analyses using bronchial epithelial cells (BEAS-2B) and alveolar type II-like cells (A549).

Results: Exposure to wood smoke increased BAL lactate dehydrogenase (LDH) (p = 0.04) and reduced the ex vivo alveolar macrophage phagocytic capacity (p = 0.03) and viability (p = 0.02) vs. filtered air. BAL eosinophil numbers were increased after wood smoke (p = 0.02), while other cell types were unaffected in BW and BAL. In vitro exposure to wood smoke particles confirmed increased DNA-damage, decreased metabolic activity and cell cycle disturbances.

Conclusions: Exposure to wood smoke from incomplete combustion did not induce any acute airway inflammatory cell influx at 6 h, apart from eosinophils. However, there were indications of a cytotoxic reaction with increased LDH, reduced cell viability and impaired alveolar macrophage phagocytic capacity. These findings are in accordance with earlier bronchoscopy findings at 24 h and may provide evidence for the increased susceptibility to infections by biomass smoke exposure, reported in population-based studies.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Air pollution, Biomass combustion, Bronchoscopy, Controlled human exposure, Cytotoxicity, In vitro, Macrophages, Phagocytosis, Wood smoke
National Category
Respiratory Medicine and Allergy Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:umu:diva-212714 (URN)10.1186/s12989-023-00541-x (DOI)37517998 (PubMedID)2-s2.0-85165871931 (Scopus ID)
Funder
Swedish Heart Lung FoundationVästerbotten County CouncilSwedish Energy AgencyUmeå University
Available from: 2023-08-15 Created: 2023-08-15 Last updated: 2023-08-15Bibliographically approved
Zhang, R., Shen, S., Wei, Y., Zhu, Y., Li, Y., Chen, J., . . . Christiani, D. C. (2022). A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians. Journal of Thoracic Oncology, 17(8), 974-990
Open this publication in new window or tab >>A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians
Show others...
2022 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 17, no 8, p. 974-990Article in journal (Refereed) Published
Abstract [en]

Introduction: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC).

Methods: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms (SNPs). Then, the top interactions were further tested by demographically adjusted logistic regression models. Finally, we used the selected interactions to build lung cancer screening models of NSCLC, separately, for never and ever smokers.

Results: With the Bonferroni correction, we identified eight statistically significant pairs of SNPs, which predominantly appeared in the 6p21.32 and 5p15.33 regions (e.g., rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.17, p = 6.57 × 10−13; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.17, p = 2.43 × 10−13; rs2858859HLA-DQA1 and rs9275572HLA-DQA2, ORinteraction = 1.15, p = 2.84 × 10−13; rs2853668TERT and rs62329694CLPTM1L, ORinteraction = 0.73, p = 2.70 × 10−13). Notably, even with much genetic heterogeneity across ethnicities, three pairs of SNPs in the 6p21.32 region identified from the European-ancestry population remained significant among an Asian population from the Nanjing Medical University Global Screening Array project (rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.13, p = 0.008; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.11, p = 5.23 × 10−4; rs3135369BTNL2 and rs9271300HLA-DQA1, ORinteraction = 0.89, p = 0.006). The interaction-empowered polygenetic risk score that integrated classical polygenetic risk score and G × G information score was remarkable in lung cancer risk stratification.

Conclusions: Important G × G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
Cancer risk, Gene-gene interaction, Genetic screening model, GWAS, Lung cancer, Single nucleotide polymorphism
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-203216 (URN)10.1016/j.jtho.2022.04.011 (DOI)000863994300009 ()35500836 (PubMedID)2-s2.0-85130893494 (Scopus ID)
Funder
NIH (National Institutes of Health)
Available from: 2023-01-17 Created: 2023-01-17 Last updated: 2023-05-22Bibliographically approved
Carlsen, H. K., Haga, S. L., Olsson, D., Behndig, A. F., Modig, L., Meister, K., . . . Olin, A.-C. (2022). Birch pollen, air pollution and their interactive effects on airway symptoms and peak expiratory flow in allergic asthma during pollen season: a panel study in Northern and Southern Sweden. Environmental Health, 21(1), Article ID 63.
Open this publication in new window or tab >>Birch pollen, air pollution and their interactive effects on airway symptoms and peak expiratory flow in allergic asthma during pollen season: a panel study in Northern and Southern Sweden
Show others...
2022 (English)In: Environmental Health, E-ISSN 1476-069X, Vol. 21, no 1, article id 63Article in journal (Refereed) Published
Abstract [en]

Background: Evidence of the role of interactions between air pollution and pollen exposure in subjects with allergic asthma is limited and need further exploration to promote adequate preventive measures. The objective of this study was to assess effects of exposure to ambient air pollution and birch pollen on exacerbation of respiratory symptoms in subjects with asthma and allergy to birch.

Methods: Thirty-seven subjects from two Swedish cities (Gothenburg and Umeå) with large variation in exposure to both birch-pollen and air pollutants, participated in the study. All subjects had confirmed allergy to birch and self-reported physician-diagnosed asthma. The subjects recorded respiratory symptoms such as rhinitis or eye irritation, dry cough, dyspnoea, the use of any asthma or allergy medication and peak respiratory flow (PEF), daily for five consecutive weeks during two separate pollen seasons and a control season without pollen. Nitrogen oxides (NOx), ozone (O3), particulate matter (PM2.5), birch pollen counts, and meteorological data were obtained from an urban background monitoring stations in the study city centres. The data were analysed using linear mixed effects models.

Results: During pollen seasons all symptoms and medication use were higher, and PEF was reduced in the subjects. In regression analysis, exposure to pollen at lags 0 to 2 days, and lags 0 to 6 days was associated with increased ORs of symptoms and decreased RRs for PEF. Pollen and air pollution interacted in some cases; during low pollen exposure, there were no associations between air pollution and symptoms, but during high pollen exposure, O3 concentrations were associated with increased OR of rhinitis or eye irritation, and PM2.5 concentrations were associated with increased ORs of rhinitis or eye irritation, dyspnea and increased use of allergy medication. Conclusions: Pollen and air pollutants interacted to increase the effect of air pollution on respiratory symptoms in allergic asthma. Implementing the results from this study, advisories for individuals with allergic asthma could be improved, minimizing the morbidities associated with the condition.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2022
Keywords
Allergic asthma, Betula, Birch, O3, Panel study, PM2.5, Pollen season
National Category
Occupational Health and Environmental Health Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-198028 (URN)10.1186/s12940-022-00871-x (DOI)000821602700002 ()2-s2.0-85133417417 (Scopus ID)
Funder
Swedish Research Council FormasSwedish Heart Lung Foundation, 2013 − 0279Swedish Heart Lung Foundation, 2016 − 0250Swedish Research Council, 210-2013-805Swedish Asthma and Allergy Association
Available from: 2022-07-15 Created: 2022-07-15 Last updated: 2023-09-05Bibliographically approved
Eriksson Ström, J., Kebede Merid, S., Pourazar, J., Blomberg, A., Lindberg, A., Ringh, M. V., . . . Melén, E. (2022). Chronic obstructive pulmonary disease is associated with epigenome-wide differential methylation in BAL lung cells. American Journal of Respiratory Cell and Molecular Biology, 66(6), 638-647
Open this publication in new window or tab >>Chronic obstructive pulmonary disease is associated with epigenome-wide differential methylation in BAL lung cells
Show others...
2022 (English)In: American Journal of Respiratory Cell and Molecular Biology, ISSN 1044-1549, E-ISSN 1535-4989, Vol. 66, no 6, p. 638-647Article in journal (Refereed) Published
Abstract [en]

DNA methylation patterns in chronic pulmonary obstructive disease (COPD) might offer new insights into disease pathogenesis. To assess methylation profiles in the main COPD target organ, we performed an epigenome-wide association study on BAL cells. Bronchoscopies were performed in 18 subjects with COPD and 15 control subjects (ex- and current smokers). DNA methylation was measured using the Illumina MethylationEPIC BeadChip Kit, covering more than 850,000 CpGs. Differentially methylated positions (DMPs) were examined for 1) enrichment in pathways and functional gene relationships using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology, 2) accelerated aging using Horvath's epigenetic clock, 3) correlation with gene expression, and 4) colocalization with genetic variation. We found 1,155 Bonferroni-significant (P < 6.74 × 10-8) DMPs associated with COPD, many with large effect sizes. Functional analysis identified biologically plausible pathways and gene relationships, including enrichment for transcription factor activity. Strong correlation was found between DNA methylation and chronological age but not between COPD and accelerated aging. For 79 unique DMPs, DNA methylation correlated significantly with gene expression in BAL cells. Thirty-nine percent of DMPs were colocalized with COPD-associated SNPs. To the best of our knowledge, this is the first epigenome-wide association study of COPD on BAL cells, and our analyses revealed many differential methylation sites. Integration with mRNA data showed a strong functional readout for relevant genes, identifying sites where DNA methylation might directly affect expression. Almost half of DMPs were colocated with SNPs identified in previous genome-wide association studies of COPD, suggesting joint genetic and epigenetic pathways related to disease.

Place, publisher, year, edition, pages
American Thoracic Society, 2022
Keywords
chronic obstructive pulmonary disease, DNA methylation, epigenetics, BAL cells, gene expression
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-201984 (URN)10.1165/rcmb.2021-0403oc (DOI)000822671800011 ()35286818 (PubMedID)2-s2.0-85131268482 (Scopus ID)
Funder
Region VästerbottenUmeå UniversitySwedish Heart Lung FoundationSwedish Research CouncilThe Kempe Foundations
Available from: 2022-12-28 Created: 2022-12-28 Last updated: 2023-09-05Bibliographically approved
Badi, Y. E., Pavel, A. B., Pavlidis, S., Riley, J. H., Bates, S., Kermani, N. Z., . . . Adcock, I. M. (2022). Mapping atopic dermatitis and anti–IL-22 response signatures to type 2–low severe neutrophilic asthma. Journal of Allergy and Clinical Immunology, 149(1), 89-101
Open this publication in new window or tab >>Mapping atopic dermatitis and anti–IL-22 response signatures to type 2–low severe neutrophilic asthma
Show others...
2022 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 149, no 1, p. 89-101Article in journal (Refereed) Published
Abstract [en]

Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.

Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti–IL-22 (fezakinumab [FZ]) is enriched in severe asthma.

Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort.

Results: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, TH2, and TH17/TH22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P <.05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P <.05) and particularly in neutrophilic and mixed granulocytic sputum (P <.05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with TH22/IL-22 pathways.

Conclusions: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
atopic dermatitis, Fezakinumab, gene set variation analysis, IL-22, severe asthma
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-184129 (URN)10.1016/j.jaci.2021.04.010 (DOI)000744544500019 ()33891981 (PubMedID)2-s2.0-85106638113 (Scopus ID)
Funder
Pfizer ABEli Lilly and CompanyEU, FP7, Seventh Framework Programme, 2007-2013
Available from: 2021-06-10 Created: 2021-06-10 Last updated: 2022-07-12Bibliographically approved
Reinke, S. N., Naz, S., Chaleckis, R., Gallart-Ayala, H., Kolmert, J., Kermani, N. Z., . . . Wheelock, C. E. (2022). Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study. European Respiratory Journal, 59(6), Article ID 2101733.
Open this publication in new window or tab >>Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study
Show others...
2022 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 59, no 6, article id 2101733Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Asthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication.

METHODS: Baseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort; 12-18-month longitudinal samples were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods.

RESULTS: A total of 90 metabolites were identified, with 40 significantly altered (p<0.05, false discovery rate <0.05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and patients with mild-to-moderate asthma differed significantly from those in patients with severe asthma (p=2.6×10-20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10-4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings.

CONCLUSIONS: This is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.

Place, publisher, year, edition, pages
NLM, 2022
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-198227 (URN)10.1183/13993003.01733-2021 (DOI)000834085100003 ()2-s2.0-85133980920 (Scopus ID)
Available from: 2022-07-21 Created: 2022-07-21 Last updated: 2023-09-05Bibliographically approved
Organisations

Search in DiVA

Show all publications