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  • 1
    In: Thorax, BMJ, Vol. 77, No. 5 ( 2022-05), p. 452-460
    Abstract: Asthma is a complex disease with heterogeneous expression/severity. There is growing interest in defining asthma endotypes consistently associated with different responses to therapy, focusing on type 2 inflammation (Th2) as a key pathological mechanism. Current asthma endotypes are defined primarily by clinical/laboratory criteria. Each endotype is likely characterised by distinct molecular mechanisms that identify optimal therapies. Methods We applied unsupervised (without a priori clinical criteria) principal component analysis on sputum airway cells RNA-sequencing transcriptomic data from 19 asthmatics from the Severe Asthma Research Program at baseline and 6–8 weeks follow-up after a 40 mg dose of intramuscular corticosteroids. We investigated principal components PC1, PC3 for association with 55 clinical variables. Results PC3 was associated with baseline Th2 clinical features including blood (rank-sum p=0.0082) and airway (rank-sum p=0.0024) eosinophilia, FEV 1 change (Kendall tau-b R=−0.333 (−0.592 to −0.012)) and follow-up FEV 1 albuterol response (Kendall tau-b R=0.392 (0.079 to 0.634)). PC1 with blood basophlia (rank-sum p=0.0191). The top 5% genes contributing to PC1, PC3 were enriched for distinct immune system/inflammation ontologies suggesting distinct subject-specific clusters of transcriptomic response to corticosteroids. PC3 association with FEV 1 change was reproduced in silico in a comparable independent 14-subject (baseline, 8 weeks after daily inhaled corticosteroids (ICS)) airway epithelial cells microRNAome dataset. Conclusions Transcriptomic PCs from this unsupervised methodology define molecular pharmacogenomic endotypes that may yield novel biology underlying different subject-specific responses to corticosteroid therapy in asthma, and optimal personalised asthma care. Top contributing genes to these PCs may suggest new therapeutic targets.
    Type of Medium: Online Resource
    ISSN: 0040-6376 , 1468-3296
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 1481491-2
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  • 2
    In: Lupus Science & Medicine, BMJ, Vol. 9, No. 1 ( 2022-06), p. e000698-
    Abstract: Despite the disproportional impact of SLE on historically marginalised communities, the individual and sociocultural factors underlying these health disparities remain elusive. We report the design and methods for a study aimed at identifying epigenetic biomarkers associated with racism and resiliency that affect gene function and thereby influence SLE in a health disparity population. Methods and analysis The Social Factors, Epigenomics and Lupus in African American Women (SELA) Study is a cross-sectional, case–control study. A total of 600 self-reported African American women will be invited to participate. All participants will respond to questionnaires that capture detailed sociodemographic and medical history, validated measures of racial discrimination, social support, as well as disease activity and damage for cases. Participants who wish will receive their genetic ancestry estimates and be involved in research. Blood samples are required to provide peripheral blood mononuclear cell counts, DNA and RNA. The primary goals of SELA are to identify variation in DNA methylation (DNAm) associated with self-reported exposure to racial discrimination and social support, to evaluate whether social DNAm sites affect gene expression, to identify the synergistic effects of social factors on DNAm changes on SLE and to develop a social factors-DNAm predictive model for disease outcomes. This study is conducted in cooperation with the Sea Island Families Project Citizen Advisory Committee. Discussion and dissemination SELA will respond to the pressing need to clarify the interplay and regulatory mechanism by which various positive and negative social exposures influence SLE. Results will be published and shared with patients and the community. Knowledge of the biological impact of social exposures on SLE, as informed by the results of this study, can be leveraged by advocacy efforts to develop psychosocial interventions that prevent or mitigate risk exposures, and services or interventions that promote positive exposures. Implementation of such interventions is paramount to the closure of the health disparities gap.
    Type of Medium: Online Resource
    ISSN: 2053-8790
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2779620-6
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