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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.)

Background: Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response., Objective: We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings., Methods: A meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10 -6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations., Results: A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10 -6 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10 -3 ) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10 -3 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified., Conclusions and Clinical Relevance: This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment., (© 2019 John Wiley & Sons Ltd.)

Aim: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium., Materials & Methods: Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire., Results: A total of 21 studies, including 14,227 children/young persons (58% male), from 12 different countries are currently enrolled in the PiCA consortium. Fifty six percent of the patients are Caucasians. In total, 7619 were inhaled corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center and the results will be meta-analyzed., Conclusion: PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population.

Background: Though the associations of CD14 with asthma have already been studied, the results of different independent studies are in conflict, mostly due to differences in the pathogenesis of varying asthma sub-phenotypes. The aim of our study was to perform an association analysis of promoter single nucleotide polymorphism (SNP) -159C/T (rs2569190) in the CD14 gene for Slovenian children with asthma., Methods: We analyzed SNP -159C/T in a group of all asthmatics, and separately in a group of atopic and non-atopic asthmatics. We also analyzed the influence of SNP -159C/T on clinical parameters and the response to therapy with inhaled corticosteroids. We have genotyped 247 children with asthma and a median age of 11 years (interquartile range, 5 years), and 158 healthy controls with a median age of 13 years (interquartile range, 5 years). We performed genotyping using a polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis., Results: We found that SNP -159C/T in CD14 is not associated with asthma in Slovenian children. However, non-atopic asthmatics with CT or TT genotypes have a lower FEV1/FVC ratio as a measure of bronchial obstruction (87.4%, compared to 91.8% in patients with the CC genotype, p = 0.017). Non-atopic asthmatics with CC or CT genotypes also have increased bronchial hyperreactivity measured by PC20 of methacholine (0.41 mg/ml, compared to 1.50 mg/ml in patients with a TT genotype, p = 0.018)., Conclusions: Our results suggest that CD14 is associated with asthma severity in Slovenian children with non-atopic asthma., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Asthma is one of the most common chronic diseases of childhood and results from the interaction of several genes and environmental influences. Interleukin 4 (IL4) and its receptor IL4R have a central role in the regulation of immunoglobulin E (IgE) production and thereby in the induction and maintenance of allergy and asthma. The single nucleotide polymorphisms (SNPs) Q551R in the IL4RA gene and C-33T in the IL4 gene probably influence IL4/IL4R pathway signaling; however, findings in association studies exploring the role of these two genes in asthma pathogenesis are contradictory. We have studied the association of IL4RA Q551R and IL4 C-33T SNPs with asthma, asthma phenotypes, and clinical and laboratory parameters., Methods: The study group comprised 106 children aged between 5 and 18 years with mild or moderate persistent asthma: 78 children were atopic and 28 had nonatopic asthma. The children underwent allergy and spirometry tests, a bronchoprovocation test with methacholine, measurement of exhaled nitric oxide in expired air and genotyping for IL4RA Q551R and IL4 C-33T SNPs. Genotype data from 89 nonatopic nonasthmatics served as a control group., Results: The frequency of the IL4RA Arg551 allele in the children with nonatopic asthma was 7.1%, significantly lower than 21.9% in the control group (P = 0.01, OR: 0.33, 95% CI: 0.12-0.87). Allelic and genotype frequencies in IL4 C-33T polymorphism in the asthma group and the control group were not significantly different. The mean value of total IgE in asthmatics with the IL4-33C allele was 556.0 IU/l, significantly higher than 371.6 IU/l in those with the T allele (P = 0.02). In an interaction study we did not find significant differences in the frequencies of any combinations of IL4RA Q551R and IL4 C-33T alleles between asthmatics and controls., Conclusions: The IL4RA Q551R SNP is associated with nonatopic asthma in Slovenian children. This finding contributes to knowledge about an important asthma phenotype pathogenesis and could serve in future research into new strategies for asthma management.

We genotyped CTLA4 CT60 (rs3087243) functional single nucleotide polymorphism (SNP) in children with asthma and in healthy controls and correlated the genotype data with asthma clinical data, including treatment response with inhaled corticosteroids measured by forced expiratory volume in the first second (FEV(1)). FEV(1) increased by 21.7% after 4 weeks of therapy in atopic asthmatics with the A/A genotype compared with an 8.6% increase in heterozygotes and a 5.8% increase in G/G homozygotes (p <0.01). Genotype and allele frequencies in asthmatics did not differ significantly from those in the control group. SNP CT60 in the CTLA4 gene is significantly associated with the response to treatment with inhaled corticosteroids in children with atopic asthma and could be a useful biomarker for personalized therapy in asthmatic children. SNP CT60 in the CTLA4 gene plays only a minor role in genetic susceptibility to childhood asthma in the Caucasian population.

Asthma is one of the most common chronic diseases of childhood. Asthma results from the interaction of several genes and environmental influences. Viral infections are common triggers of asthma attacks, especially in nonatopic asthmatics. CCR5 is a chemokine receptor involved in the immune response against a number of viruses. A 32 base pair deletion (delta32) in the CCR5 receptor gene causes loss of gene function and is associated with several chronic diseases due to the resulting altered immunity. The results of the association studies exploring the role of the CCR5 receptor gene in asthma pathogenesis are contradictory. We studied 111 children aged between 5 and 18 years with mild or moderate persistent asthma; 75 of them were atopic and 36 had nonatopic asthma. We carried out allergy and spirometry tests, a bronchoprovocation test with methacholine and performed measurement of exhaled nitric oxide and genotyping for CCR5-delta32 mutation. Compared with 365 nonatopic, nonasthmatic controls we found significantly lower CCR5-delta32 allelic frequency in nonatopic asthmatics (p = 0.016, OR 0.139, 95% CI 0.02 to 0.984) but not in atopic asthmatics. CCR5-delta32 mutation protects against nonatopic asthma. This association offers new insights into the pathogenesis of an important asthma phenotype and could serve as useful information for the future research of new asthma management strategies.

Asthma is the most prevalent pediatric chronic disease. Bronchodilator drug response (BDR) and fractional exhaled nitric oxide (FeNO) are clinical biomarkers of asthma. Although DNA methylation (DNAm) contributes to asthma pathogenesis, the influence of DNAm on BDR and FeNO is scarcely investigated. This study aims to identify DNAm markers in whole blood associated either with BDR or FeNO in pediatric asthma. We analyzed 121 samples from children with moderate-to-severe asthma. The association of genome-wide DNAm with BDR and FeNO has been assessed using regression models, adjusting for age, sex, ancestry, and tissue heterogeneity. Cross-tissue validation was assessed in 50 nasal samples. Differentially methylated regions (DMRs) and enrichment in traits and biological pathways were assessed. A false discovery rate (FDR) < 0.1 and a genome-wide significance threshold of p < 9 × 10−8 were used to control for false-positive results. The CpG cg12835256 (PLA2G12A) was genome-wide associated with FeNO in blood samples (coefficient= −0.015, p = 2.53 × 10−9) and nominally associated in nasal samples (coefficient = −0.015, p = 0.045). Additionally, three CpGs were suggestively associated with BDR (FDR < 0.1). We identified 12 and four DMRs associated with FeNO and BDR (FDR < 0.05), respectively. An enrichment in allergic and inflammatory processes, smoking, and aging was observed. We reported novel associations of DNAm markers associated with BDR and FeNO enriched in asthma-related processes. [ABSTRACT FROM AUTHOR]

Inhaled corticosteroids (ICS) are the most common asthma controller medication. An important contribution of genetic factors in ICS response has been evidenced. Here, we aimed to identify novel genetic markers involved in ICS response in asthma. A genome-wide association study (GWAS) of the change in lung function after 6 weeks of ICS treatment was performed in 166 asthma patients from the SLOVENIA study. Patients with an improvement in lung function ≥8% were considered as ICS responders. Suggestively associated variants (p-value ≤ 5 × 10−6) were evaluated in an independent study (n = 175). Validation of the association with asthma exacerbations despite ICS use was attempted in European (n = 2681) and admixed (n = 1347) populations. Variants previously associated with ICS response were also assessed for replication. As a result, the SNP rs1166980 from the ROBO2 gene was suggestively associated with the change in lung function (OR for G allele: 7.01, 95% CI: 3.29–14.93, p = 4.61 × 10−7), although this was not validated in CAMP. ROBO2 showed gene-level evidence of replication with asthma exacerbations despite ICS use in Europeans (minimum p-value = 1.44 × 10−5), but not in admixed individuals. The association of PDE10A-T with ICS response described by a previous study was validated. This study suggests that ROBO2 could be a potential novel locus for ICS response in Europeans. [ABSTRACT FROM AUTHOR]