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BackgroundHereditary angioedema is a rare genetic condition caused by C1 esterase inhibitor deficiency, dysfunction, or kinin cascade dysregulation, leading to an increased bradykinin plasma concentration. Hereditary angioedema is a poorly recognized clinical entity and is very often misdiagnosed as a histaminergic angioedema. Despite its genetic nature, first-line genetic screening is not integrated in routine diagnosis. Consequently, a delay in the diagnosis, and inaccurate or incomplete diagnosis and treatment of hereditary angioedema are common. ObjectiveIn agreement with recent recommendations from the International Consensus on the Use of Genetics in the Management of Hereditary Angioedema, to facilitate the clinical diagnosis and adapt it to the paradigm of precision medicine and next-generation sequencing–based genetic tests, we aimed to develop a genetic annotation tool, termed Hereditary Angioedema Database Annotation (HADA). MethodsHADA is built on top of a database of known variants affecting function, including precomputed pathogenic assessment of each variant and a ranked classification according to the current guidelines from the American College of Medical Genetics and Genomics. ResultsHADA is provided as a freely accessible, user-friendly web-based interface with versatility for the entry of genetic information. The underlying database can also be incorporated into automated command-line stand-alone annotation tools. ConclusionsHADA can achieve the rapid detection of variants affecting function for different hereditary angioedema types, and further integrates useful information to reduce the diagnosis odyssey and improve its delay.

Author(s): Beatriz Guillen-Guio [sup.1], Tamara Hernandez-Beeftink, Laura Ciuffreda, Héctor Rodríguez-Pérez, David Domínguez, Adrian Baez-Ortega, Almudena Corrales, Raúl Hernández-Bisshopp, Jorge Arias, Luis Soto, David Viera Camacho, Gabriela Noemí González, Marina Soro, [...]

Differentially expressed genes in the discovery were examined to determine whether they also showed changes in peripheral blood mononuclear cells (PBMCs) obtained from ICS non-responders (n = 3) and ICS responders (n = 3) from the SLOVENIA study,4 defined based on the presence or absence of asthma exacerbations despite ICS therapy. Asthma treatment, childhood asthma, exacerbations, genetic polymorphism, pharmacogenomics Keywords: asthma treatment; childhood asthma; exacerbations; genetic polymorphism; pharmacogenomics EN asthma treatment childhood asthma exacerbations genetic polymorphism pharmacogenomics 1238 1243 6 04/14/21 20210401 NES 210401 To the Editor, An increasing number of therapies are available to treat asthma, but inhaled corticosteroids (ICS) are still the most commonly prescribed and effective controller asthma medication.1 Both environmental and genetic factors are involved in ICS response. Details about each study are described at the Supporting Information and elsewhere.4 Individuals with asthma exacerbations despite ICS treatment were considered as ICS non-responders and those without asthma exacerbations as ICS responders. [Extracted from the article]

Background: Toll-like receptors (TLRs) are critical components for host pathogen recognition and variants in genes participating in this response influence susceptibility to infections. Recently, TLR1 gene polymorphisms have been found correlated with whole blood hyper-inflammatory responses to pathogen-associated molecules and associated with sepsisassociated multiorgan dysfunction and acute lung injury (ALI). We examined the association of common variants of TLR1 gene with sepsis-derived complications in an independent study and with serum levels for four inflammatory biomarkers among septic patients. Methodology/Principal Findings: Seven tagging single nucleotide polymorphisms of the TLR1 gene were genotyped in samples from a prospective multicenter case-only study of patients with severe sepsis admitted into a network of intensive care units followed for disease severity. Interleukin (IL)-1&≤x03B2;, IL-6, IL-10, and C-reactive protein (CRP) serum levels were measured at study entry, at 48 h and at 7th day. Alleles -7202G and 248Ser, and the 248Ser-602Ile haplotype were associated with circulatory dysfunction among severe septic patients (0.001≤p≤0.022), and with reduced IL-10 (0.012≤p≤0.047) and elevated CRP (0.011≤p≤0.036) serum levels during the first week of sepsis development. Additionally, the -7202GG genotype was found to be associated with hospital mortality (p = 0.017) and ALI (p = 0.050) in a combined analysis with European Americans, suggesting common risk effects among studies. Conclusions/Significance: These results partially replicate and extend previous findings, supporting that variants of TLR1 gene are determinants of severe complications during sepsis. [ABSTRACT FROM AUTHOR]

Rationale: Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies., Methods: A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 children of European descent treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed., Results: 10 independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10 -6 ). Of those, one variant at the CACNA2D3-WNT5A locus was nominally replicated in Europeans (rs67026078; p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found., Conclusions: The intergenic region of CACNA2D3 and WNT5A was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response., Competing Interests: Conflict of interest: N. Hernandez-Pacheco reports grants from Instituto de Salud Carlos III (ISCIII, FI16/00136) and co-funded by the European Social Funds from the European Union (ESF) “ESF invests in your future”, during the conduct of the study. Conflict of interest: S.J. Vijverberg has nothing to disclose. Conflict of interest: E. Herrera-Luis reports grants from the Spanish Ministry of Science, Innovation, and Universities (PRE2018-083837), during the conduct of the study. Conflict of interest: J. Li has nothing to disclose. Conflict of interest: Y.Y. Sio has nothing to disclose. Conflict of interest: R. Granell has nothing to disclose. Conflict of interest: A. Corrales has nothing to disclose. Conflict of interest: C. Maroteau has nothing to disclose. Conflict of interest: R. Lethem has nothing to disclose. Conflict of interest: J. Perez-Garcia has nothing to disclose. Conflict of interest: N. Farzan has nothing to disclose. Conflict of interest: K. Repnik has nothing to disclose. Conflict of interest: M. Gorenjak has nothing to disclose. Conflict of interest: P. Soares has nothing to disclose. Conflict of interest: L. Karimi has nothing to disclose. Conflict of interest: M. Schieck has nothing to disclose. Conflict of interest: L. Pérez-Méndez has nothing to disclose. Conflict of interest: V. Berce has nothing to disclose. Conflict of interest: R. Tavendale has nothing to disclose. Conflict of interest: C. Eng has nothing to disclose. Conflict of interest: O. Sardon has nothing to disclose. Conflict of interest: I. Kull has nothing to disclose. Conflict of interest: S. Mukhopadhyay reports grants from The Gannochy Trust, Perth and Kinross City Council and Scottish Enterprises Tayside, during the conduct of the study. Conflict of interest: M. Pirmohamed reports grants from UK Department of Health and UK Medical Research Council, during the conduct of the study; grants from MRC Clinical Pharmacology Training Scheme (joint funding by MRC and Roche, UCB, Eli Lilly and Novartis), Joint PhD studentship funded by EPSRC and Astra Zeneca and grants from Bristol Myers Squibb, outside the submitted work. Conflict of interest: K.M.C. Verhamme reports grants from ZonMw, during the conduct of the study; and works for a department who in the past received unconditional research grants from Yamanouchi, Pfizer/Boehringer Ingelheim, Novartis and GSK. Conflict of interest: E.G. Burchard reports grants from the National Heart, Lung, and Blood Institute (NHLBI) of the US National Institutes of Health (NIH) (X01HL134589, X01HL134589,R01HL128439, R01HL135156, R01HL141992 and R01HL141845), the National Institute of Environmental Health Sciences (NIEHS) (R01ES015794 and R21ES24844), the National Institute on Minority Health and Health Disparities (NIMHD) (P60MD006902, R01MD010443 and R56MD013312), the National Institute of General Medical Sciences (NIGMS) (RL5GM118984), the Tobacco-Related Disease Research Program (award numbers 24RT-0025 and 27IR-0030), the National Human Genome Research Institute (NHGRI) (U01HG009080), the Sandler Family Foundation, the American Asthma Foundation, the Amos Medical Faculty Development Program from the Robert Wood Johnson Foundation, the Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences II, during the conduct of the study. Conflict of interest: M. Kabesch reports grants from European Union, German Ministry of Education and Research, German Research Foundation, during the conduct of the study; personal fees for consultancy from Bionorica, Sanofi, Novartis and Bencard, personal fees for lectures from ERS, EAACI, ATS, Novartis, Glaxo, Nutricia, Hipp and Allergopharma, outside the submitted work. Conflict of interest: D.B. Hawcutt has nothing to disclose. Conflict of interest: E. Melén has nothing to disclose. Conflict of interest: U. Potočnik reports grants from Slovenian Research Agency (P3-0067) and Ministry of Education, Science and Sport Slovenia (MIZS) (SysPharmPediA grant C3330-16-500106), during the conduct of the study. Conflict of interest: F.T. Chew reports grants from Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network, National Medical Research Council (NMRC) (Singapore), Biomedical Research Council (BMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore), during the conduct of the study; and consulting fees from Sime Darby Technology Centre, First Resources Ltd, Genting Plantation and Olam International, outside the submitted work. Conflict of interest: K.G. Tantisira reports grants from U.S. National Institutes of Health, during the conduct of the study. Conflict of interest: S. Turner has nothing to disclose. Conflict of interest: C.M. Palmer has nothing to disclose. Conflict of interest: C. Flores has nothing to disclose. Conflict of interest: M. Pino-Yanes reports grants from Spanish Ministry of Economy, Industry and Competitiveness (funded by the Ramón y Cajal Program, RYC-2015-17205), and Instituto de Salud Carlos III (ISCIII) (funded by ISCIII through AES and EC within AAL framework, and the SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020, AC15/00015), during the conduct of the study. Conflict of interest: A.H. Maitland-van der Zee reports grants from GSK, during the conduct of the study; grants from Boehringer Ingelheim, personal fees for advisory board work from AstraZeneca and Boehringer Ingelheim, outside the submitted work., (Copyright ©ERS 2021.)

The prevalence of asthma symptoms in Canary Islanders, a southwestern European population from Spain, is almost three times higher than the country average. Because the genetic risks identified so far explain <5% of asthma heritability, here we aimed to discover new asthma loci by completing the first admixture mapping study in Canary Islanders leveraging their distinctive genetic makeup, where significant northwest African influences coexist in the European genetic diversity landscape. A 2-stage study was conducted in 1,491 unrelated individuals self-declaring having a Canary Islands origin for the 4 grandparents. Local ancestry estimates were obtained for the shared positions with reference data from putative ancestral populations from Europe, North Africa, and sub-Saharan Africa. Case-control deviations in local ancestry were tested for each ancestry separately using logistic regressions adjusted for principal components, followed by fine-mapping analyses based on imputed genotypes and analyses of the likely deleterious exonic variants. The admixture mapping analysis of asthma detected that local North African ancestry in a locus spanning 365 kb of chromosome 16q23.3 was associated with asthma risk at study-wide significance [lowest P = 1.12 × 10 -4 ; odds ratio (OR) = 2.05; 95% confidence interval (CI) = 1.41-3.00]. Fine-mapping studies identified a variant associated with asthma, and results were replicated in independent samples (rs3852738, OR = 1.34; 95% CI = 1.13-1.59, P = 7.58 × 10 -4 ). Whole exome sequencing data from a subset of individuals revealed an enrichment of likely deleterious variants among asthma cases in 16q23.3, particularly in the phospholipase Cγ2 ( PLCG2 ) gene ( P = 3.67 × 10 -4 ). By completing the first mapping study of asthma in admixed populations from Europe, our results revealed a new plausible asthma locus.