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- Mathey, Carina M, et al.
(författare)
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Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes
- 2022
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Ingår i: Frontiers in Genetics. - : Frontiers Media S.A.. - 1664-8021. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Angioedema is a relatively rare but potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). As with hereditary forms of angioedema (HAE), this adverse reaction is mediated by bradykinin. Research suggests that ACEi/ARB-induced angioedema has a multifactorial etiology. In addition, recent case reports suggest that some ACEi/ARB-induced angioedema patients may carry pathogenic HAE variants. The aim of the present study was to investigate the possible association between ACEi/ARB-induced angioedema and HAE genes via systematic molecular genetic screening in a large cohort of ACEi/ARB-induced angioedema cases. Targeted re-sequencing of five HAE-associated genes (SERPING1, F12, PLG, ANGPT1, and KNG1) was performed in 212 ACEi/ARB-induced angioedema patients recruited in Germany/Austria, Sweden, and Denmark, and in 352 controls from a German cohort. Among patients, none of the identified variants represented a known pathogenic variant for HAE. Moreover, no significant association with ACEi/ARB-induced angioedema was found for any of the identified common [minor allele frequency (MAF) >5%] or rare (MAF < 5%) variants. However, several non-significant trends suggestive of possible protective effects were observed. The lowest p-value for an individual variant was found in PLG (rs4252129, p.R523W, p = 0.057, p.adjust > 0.999, Fisher's exact test). Variant p.R523W was found exclusively in controls and has previously been associated with decreased levels of plasminogen, a precursor of plasmin which is part of a pathway directly involved in bradykinin production. In addition, rare, potentially functional variants (MAF < 5%, Phred-scaled combined annotation dependent depletion score >10) showed a nominally significant enrichment in controls both: 1) across all five genes; and 2) in the F12 gene alone. However, these results did not withstand correction for multiple testing. In conclusion, our results suggest that HAE-associated mutations are, at best, a rare cause of ACEi/ARB-induced angioedema. Furthermore, we were unable to identify a significant association between ACEi/ARB-induced angioedema and other variants in the investigated genes. Further studies with larger sample sizes are warranted to draw more definite conclusions concerning variants with limited effect sizes, including protective variants.
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- Forkel, M., et al.
(författare)
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Identifying environmental controls on vegetation greenness phenology through model-data integration
- 2014
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 11:23, s. 7025-7050
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Tidskriftsartikel (refereegranskat)abstract
- Existing dynamic global vegetation models (DGVMs) have a limited ability in reproducing phenology and decadal dynamics of vegetation greenness as observed by satellites. These limitations in reproducing observations reflect a poor understanding and description of the environmental controls on phenology, which strongly influence the ability to simulate longer-term vegetation dynamics, e.g. carbon allocation. Combining DGVMs with observational data sets can potentially help to revise current modelling approaches and thus enhance the understanding of processes that control seasonal to long-term vegetation greenness dynamics. Here we implemented a new phenology model within the LPJmL (Lund Potsdam Jena managed lands) DGVM and integrated several observational data sets to improve the ability of the model in reproducing satellite-derived time series of vegetation greenness. Specifically, we optimized LPJmL parameters against observational time series of the fraction of absorbed photosynthetic active radiation (FAPAR), albedo and gross primary production to identify the main environmental controls for seasonal vegetation greenness dynamics. We demonstrated that LPJmL with new phenology and optimized parameters better reproduces seasonality, inter-annual variability and trends of vegetation greenness. Our results indicate that soil water availability is an important control on vegetation phenology not only in water-limited biomes but also in boreal forests and the Arctic tundra. Whereas water availability controls phenology in water-limited ecosystems during the entire growing season, water availability co-modulates jointly with temperature the beginning of the growing season in boreal and Arctic regions. Additionally, water availability contributes to better explain decadal greening trends in the Sahel and browning trends in boreal forests. These results emphasize the importance of considering water availability in a new generation of phenology modules in DGVMs in order to correctly reproduce observed seasonal-to-decadal dynamics of vegetation greenness.
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- Parigi, Sara M., et al.
(författare)
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Flt3 ligand expands bona fide innate lymphoid cell precursors in vivo
- 2018
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- A common helper-like innate lymphoid precursor (CHILP) restricted to the innate lymphoid cells (ILC) lineage has been recently characterized. While specific requirements of transcription factors for CHILPs development has been partially described, their ability to sense cytokines and react to peripheral inflammation remains unaddressed. Here, we found that systemic increase in Flt3L levels correlated with the expansion of Lineage (Lin)(neg)alpha 4 beta 7(+) precursors in the adult murine bone marrow. Expanded Lin(neg)alpha 4 beta 7(+) precursors were bona fide CHILPs as seen by their ability to differentiate into all helper ILCs subsets but cNK in vivo. Interestingly, Flt3L-expanded CHILPs transferred into lymphopenic mice preferentially reconstituted the small intestine. While we did not observe changes in serum Flt3L during DSS-induced colitis in mice or plasma from inflammatory bowel disease (IBD) patients, elevated Flt3L levels were detected in acute malaria patients. Interestingly, while CHILP numbers were stable during the course of DSS-induced colitis, they expanded following increased serum Flt3L levels in malaria-infected mice, hence suggesting a role of the Flt3L-ILC axis in malaria. Collectively, our results indicate that Flt3L expands CHILPs in the bone marrow, which might be associated with specific inflammatory conditions.
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