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1.
Clin Exp Allergy ; 53(2): 186-197, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36104952

RESUMEN

BACKGROUND: Few biomarkers identify eosinophilic and neutrophilic asthma beyond cell concentrations in blood or sputum. Finding novel biomarkers for asthma endotypes could give insight about disease mechanisms and guide tailored treatment. Our aim was to investigate clinical characteristics and inflammation-related plasma proteins in relation to blood eosinophil and neutrophil concentrations in subjects with and without asthma. METHODS: We included 24-26-year-old subjects (n = 2063) from the Swedish population-based cohort BAMSE. Subjects with asthma (n = 239) and without asthma (n = 1824) were subdivided based on blood eosinophil and neutrophil concentrations (cut-offs 0.3 × 109 /L and 5.0 × 109 /L, respectively). We measured the levels of 92 plasma proteins using Olink Proseek Multiplex Inflammation Panel Assay. Group statistics tests were used to analyse the data, as well as adjusted multiple logistic regression models. RESULTS: Among subjects with asthma, 21.8% had eosinophilic asthma and 20.5% neutrophilic asthma. Eosinophilic asthma, but not neutrophilic asthma, was associated with a distinct clinical phenotype with, for example, higher proportions of eczema and sensitization. Most plasma proteins that associated with high eosinophil and/or neutrophil blood concentrations in subjects with asthma showed similar associations in subjects without asthma. However, out of these proteins, MMP10 levels were associated with eosinophilic asthma and were significantly higher as compared to controls with high eosinophilic concentration, while CCL4 levels associated with high neutrophil concentration only in subjects with asthma. CONCLUSIONS: Eosinophilic asthma was associated with a clear clinical phenotype. With our definitions, we identified MMP10 as a possible plasma biomarker for eosinophilic asthma and CCL4 was linked to neutrophilic asthma. These proteins should be evaluated further in clinical settings and using sputum granulocytes to define the asthma endotypes.


Asunto(s)
Asma , Eosinófilos , Neutrófilos , Humanos , Asma/diagnóstico , Asma/metabolismo , Asma/patología , Biomarcadores/metabolismo , Eosinofilia/metabolismo , Eosinófilos/metabolismo , Eosinófilos/patología , Inflamación/diagnóstico , Inflamación/metabolismo , Metaloproteinasa 10 de la Matriz/química , Metaloproteinasa 10 de la Matriz/metabolismo , Neutrófilos/metabolismo , Neutrófilos/patología , Proteómica , Esputo
2.
J Allergy Clin Immunol ; 149(6): 1981-1991, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-34971648

RESUMEN

BACKGROUND: Inhaled corticosteroid (ICS) response among patients with asthma is influenced by genetics, but biologically actionable insights based on associations have not been found. Various glucocorticoid response omics data sets are available to interrogate their biological effects. OBJECTIVE: We sought to identify functionally relevant ICS-response genetic associations by integrating complementary multiomics data sets. METHODS: Variants with P values less than 10-4 from a previous ICS-response genome-wide association study were reranked on the basis of integrative scores determined from (1) glucocorticoid receptor- and (2) RNA polymerase II-binding regions inferred from ChIP-Seq data for 3 airway cell types, (3) glucocorticoid response element motifs, (4) differentially expressed genes in response to glucocorticoid exposure according to 20 transcriptomic data sets, and (5) expression quantitative trait loci from GTEx. Candidate variants were tested for association with ICS response and asthma in 6 independent studies. RESULTS: Four variants had significant (q value < 0.05) multiomics integrative scores. These variants were in a locus consisting of 52 variants in high linkage disequilibrium (r2 ≥ 0.8) near glucocorticoid receptor-binding sites by the gene BIRC3. Variants were also BIRC3 expression quantitative trait loci in lung, and 2 were within/near putative glucocorticoid response element motifs. BIRC3 had increased RNA polymerase II occupancy and gene expression, with glucocorticoid exposure in 2 ChIP-Seq and 13 transcriptomic data sets. Some BIRC3 variants in the 52-variant locus were associated (P < .05) with ICS response in 3 independent studies and others with asthma in 1 study. CONCLUSIONS: BIRC3 should be prioritized for further functional studies of ICS response.


Asunto(s)
Asma , Glucocorticoides , Corticoesteroides , Asma/genética , Asma/metabolismo , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/genética , Estudio de Asociación del Genoma Completo , Glucocorticoides/farmacología , Humanos , Pulmón/metabolismo , Polimorfismo de Nucleótido Simple , ARN Polimerasa II/genética , Receptores de Glucocorticoides/genética
3.
Pediatr Allergy Immunol ; 33(5): e13780, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35616899

RESUMEN

Investigation of gene-environment interactions (GxE) may provide important insights into the gene regulatory framework in response to environmental factors of relevance for childhood asthma. Over the years, different methodological strategies have been applied, more recently using genome-wide approaches. The best example to date is the major asthma locus on the 17q12-21 chromosome region, viral infections, and airway epithelium processes where recent studies have shed much light on mechanisms in childhood asthma. However, there are challenges with the traditional single variant-single exposure interaction models, as they do not encompass the complexity and cumulative effects of multiple exposures or multiple genetic variants. As such, we need to redefine our traditional GxE thinking, and we propose in this review to expand the GxE concept by also evaluating other omics layers, such as epigenetics, transcriptomics, metabolomics, and proteomics. In addition, host factors such as age, gender, and other exposures are very likely to influence GxE effects and need firmly to be considered in future studies.


Asunto(s)
Asma , Interacción Gen-Ambiente , Asma/genética , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Metabolómica
4.
Pediatr Allergy Immunol ; 33(6): e13802, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35754128

RESUMEN

BACKGROUND: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. METHODS: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10-5 ) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. RESULTS: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele ) = 0.82, p = 9.05 × 10-6 and replication: ORT allele  = 0.89, p = 5.35 × 10-3 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele  = 0.85, p = 3.10 × 10-5 and replication: ORC allele  = 0.89, p = 1.30 × 10-2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. CONCLUSIONS: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.


Asunto(s)
Asma , Estudio de Asociación del Genoma Completo , Asma/genética , Predisposición Genética a la Enfermedad , Hispánicos o Latinos/genética , Humanos , Polimorfismo de Nucleótido Simple , Calidad de Vida
5.
Eur Respir J ; 57(5)2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33303529

RESUMEN

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.


Asunto(s)
Antiasmáticos , Asma , Administración por Inhalación , Corticoesteroides/uso terapéutico , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Niño , Estudio de Asociación del Genoma Completo , Humanos , Adulto Joven
6.
Clin Exp Allergy ; 51(9): 1157-1171, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34128573

RESUMEN

BACKGROUND: The polymorphism Arg16 in ß2 -adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting ß2 -agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27. OBJECTIVE: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA. METHODS: The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma-related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta-analysed using the inverse variance weighting method assuming random-effects. RESULTS: In subjects treated with ICS and LABA (n = 832, age: 3-21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05-1.87, I2  = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05-1.94, I2  = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71-1.39, I2  = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as-required short-acting ß2 -agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686). CONCLUSION AND CLINICAL RELEVANCE: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype-guided treatment which might improve clinical outcomes in asthmatic patients.


Asunto(s)
Asma/genética , Asma/fisiopatología , Receptores Adrenérgicos beta 2/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Genotipo , Humanos , Masculino , Polimorfismo Genético/genética , Adulto Joven
7.
Pediatr Allergy Immunol ; 32(6): 1197-1207, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33706416

RESUMEN

BACKGROUND: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium. METHODS: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma. RESULTS: Genome-wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10-6 ) associated with exacerbations despite LABA use. CONCLUSION: No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.


Asunto(s)
Antiasmáticos , Asma , Administración por Inhalación , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/genética , Niño , Estudio de Asociación del Genoma Completo , Humanos , Adulto Joven
9.
Pharmacogenomics J ; 20(5): 621-628, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-31949291

RESUMEN

A systematic review of pharmacogenomic studies capturing adverse drug reactions (ADRs) related to asthma medications was undertaken, and a survey of Pharmacogenomics in Childhood Asthma (PiCA) consortia members was conducted. Studies were eligible if genetic polymorphisms were compared with suspected ADR(s) in a patient with asthma, as either a primary or secondary outcome. Five studies met the inclusion criteria. The ADRs and polymorphisms identified were change in lung function tests (rs1042713), adrenal suppression (rs591118), and decreased bone mineral density (rs6461639) and accretion (rs9896933, rs2074439). Two of these polymorphisms were replicated within the paper, but none had external replication. Priorities from PiCA consortia members (representing 15 institution in eight countries) for future studies were tachycardia (SABA/LABA), adrenal suppression/crisis and growth suppression (corticosteroids), sleep/behaviour disturbances (leukotriene receptor antagonists), and nausea and vomiting (theophylline). Future pharmacogenomic studies in asthma should collect relevant ADR data as well as markers of efficacy.


Asunto(s)
Antiasmáticos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Niño , Preescolar , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Farmacogenómica , Fenotipo , Medición de Riesgo , Factores de Riesgo , Adulto Joven
10.
J Allergy Clin Immunol ; 143(5): 1791-1802, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30367910

RESUMEN

BACKGROUND: Although inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved nonwhite populations. OBJECTIVE: We sought to identify genetic predictors of ICS response in multiple population groups with asthma. METHODS: The discovery group comprised African American participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) who underwent 6 weeks of monitored ICS therapy (n = 244). A genome-wide scan was performed to identify single nucleotide polymorphism (SNP) variants jointly associated (ie, the combined effect of the SNP and SNP × ICS treatment interaction) with changes in asthma control. Top associations were validated by assessing the joint association with asthma exacerbations in 3 additional groups: African Americans (n = 803 and n = 563) and Latinos (n = 1461). RNA sequencing data from 408 asthmatic patients and 405 control subjects were used to examine whether genotype was associated with gene expression. RESULTS: One variant, rs3827907, was significantly associated with ICS-mediated changes in asthma control in the discovery set (P = 7.79 × 10-8) and was jointly associated with asthma exacerbations in 3 validation cohorts (P = .023, P = .029, and P = .041). RNA sequencing analysis found the rs3827907 C-allele to be associated with lower RNASE2 expression (P = 6.10 × 10-4). RNASE2 encodes eosinophil-derived neurotoxin, and the rs3827907 C-allele appeared to particularly influence ICS treatment response in the presence of eosinophilic inflammation (ie, high pretreatment eosinophil-derived neurotoxin levels or blood eosinophil counts). CONCLUSION: We identified a variant, rs3827907, that appears to influence response to ICS treatment in multiple population groups and likely mediates its effect through eosinophils.


Asunto(s)
Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Negro o Afroamericano , Neurotoxina Derivada del Eosinófilo/genética , Eosinófilos/inmunología , Genotipo , Hispánicos o Latinos , Adolescente , Adulto , Asma/epidemiología , Asma/genética , Niño , Estudios de Cohortes , Progresión de la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Recuento de Leucocitos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Variantes Farmacogenómicas , Fenotipo , Polimorfismo de Nucleótido Simple , Resultado del Tratamiento , Estados Unidos/epidemiología , Adulto Joven
11.
Clin Exp Allergy ; 49(6): 789-798, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30697902

RESUMEN

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.


Asunto(s)
Corticoesteroides/administración & dosificación , Asma/genética , Citidina Desaminasa/genética , Proteínas de Unión al ADN/genética , Proteínas Activadoras de GTPasa/genética , Estudio de Asociación del Genoma Completo , Antígenos de Histocompatibilidad Menor/genética , Administración por Inhalación , Adolescente , Asma/metabolismo , Niño , Femenino , Humanos , Masculino
12.
BMC Genet ; 20(1): 59, 2019 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-31315583

RESUMEN

BACKGROUND: Association studies in recently admixed populations are extremely useful to identify the genetic architecture of pigmentation, due to their high genotypic and phenotypic variation. However, to date only four Genome-Wide Association Studies (GWAS) have been carried out in these populations. RESULTS: We present a GWAS of skin pigmentation in an admixed sample from Cuba (N = 762). Additionally, we conducted a meta-analysis including the Cuban sample, and admixed samples from Cape Verde, Puerto Rico and African-Americans from San Francisco. This meta-analysis is one of the largest efforts so far to characterize the genetic basis of skin pigmentation in admixed populations (N = 2,104). We identified five genome-wide significant regions in the meta-analysis, and explored if the markers observed in these regions are associated with the expression of relevant pigmentary genes in human melanocyte cultures. In three of the regions identified in the meta-analysis (SLC24A5, SLC45A2, and GRM5/TYR), the association seems to be driven by non-synonymous variants (rs1426654, rs16891982, and rs1042602, respectively). The rs16891982 polymorphism is strongly associated with the expression of the SLC45A2 gene. In the GRM5/TYR region, in addition to the rs1042602 non-synonymous SNP located on the TYR gene, variants located in the nearby GRM5 gene have an independent effect on pigmentation, possibly through regulation of gene expression of the TYR gene. We also replicated an association recently described near the MFSD12 gene on chromosome 19 (lead variant rs112332856). Additionally, our analyses support the presence of multiple signals in the OCA2/HERC2/APBA2 region on chromosome 15. A clear causal candidate is the HERC2 intronic variant rs12913832, which has a profound influence on OCA2 expression. This variant has pleiotropic effects on eye, hair, and skin pigmentation. However, conditional and haplotype-based analyses indicate the presence of other variants with independent effects on melanin levels in OCA2 and APBA2. Finally, a follow-up of genome-wide signals identified in a recent GWAS for tanning response indicates that there is a substantial overlap in the genetic factors influencing skin pigmentation and tanning response. CONCLUSIONS: Our meta-analysis of skin pigmentation GWAS in recently admixed populations provides new insights about the genetic architecture of this complex trait.


Asunto(s)
Genética de Población , Estudio de Asociación del Genoma Completo , Pigmentación de la Piel/genética , Alelos , Genotipo , Humanos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo
13.
Curr Opin Pulm Med ; 25(1): 101-112, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30334825

RESUMEN

PURPOSE OF REVIEW: Asthma exacerbations have been suggested to result from complex interactions between genetic and nongenetic components. In this review, we provide an overview of the genetic association studies of asthma exacerbations, their main results and limitations, as well as future directions of this field. RECENT FINDINGS: Most studies on asthma exacerbations have been performed using a candidate-gene approach. Although few genome-wide association studies of asthma exacerbations have been conducted up to date, they have revealed promising associations but with small effect sizes. Additionally, the analysis of interactions between genetic and environmental factors has contributed to better understand of genotype-specific responses in asthma exacerbations. SUMMARY: Genetic association studies have allowed identifying the 17q21 locus and the ADRB2 gene as the loci most consistently associated with asthma exacerbations. Future studies should explore the full spectrum of genetic variation and will require larger sample sizes, a better representation of racial/ethnic diversity and a more precise definition of asthma exacerbations. Additionally, the analysis of important environmental gene-environment analysis and the integration of multiple omics will allow understanding the genetic factors and biological processes underlying the risk for asthma exacerbations.


Asunto(s)
Asma/genética , Genómica , Brote de los Síntomas , Asma/tratamiento farmacológico , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Farmacogenética
15.
Curr Allergy Asthma Rep ; 16(8): 53, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27393700

RESUMEN

Differences in asthma prevalence have been described across different populations, suggesting that genetic ancestry can play an important role in this disease. In fact, several studies have demonstrated an association between African ancestry with increased asthma susceptibility and severity, higher immunoglobulin E levels, and lower lung function. In contrast, Native American ancestry has been shown to have a protective role for this disease. Genome-wide association studies have allowed the identification of population-specific genetic variants with varying allele frequency among populations. Additionally, the correlation of genetic ancestry at the chromosomal level with asthma and related traits by means of admixture mapping has revealed regions of the genome where ancestry is correlated with the disease. In this review, we discuss the evidence supporting the association of genetic ancestry with asthma susceptibility and asthma-related traits, and highlight the regions of the genome harboring ancestry-specific genetic risk factors.


Asunto(s)
Asma/epidemiología , Asma/genética , Predisposición Genética a la Enfermedad/etnología , Estudio de Asociación del Genoma Completo , Población Negra , Humanos , Prevalencia
17.
Biomedicines ; 12(5)2024 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-38791024

RESUMEN

Asthma is a heterogeneous respiratory disease that represents a substantial social and economic burden [...].

18.
Clin Transl Allergy ; 13(3): e12238, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36973952

RESUMEN

BACKGROUND: Obese asthma is a complex phenotype and further characterization of the pathophysiology is needed. This study aimed to explore inflammation-related plasma biomarkers in lean and overweight/obese asthmatics. METHODS: We elucidated levels of inflammation-related plasma proteins in obese asthma phenotypes in the population-based cohort BAMSE (Swedish: Children, Allergy, Milieu, Stockholm, Epidemiology) using data from 2069 24-26-year-olds. Subjects were divided into lean asthma (n = 166), lean controls (n = 1440), overweight/obese asthma (n = 73) and overweight/obese controls (n = 390). Protein levels (n = 92) were analysed using the Olink Proseek Multiplex Inflammation panel. RESULTS: Of the 92 included proteins, 41 were associated with lean and/or overweight/obese asthma. The majority of proteins associated with overweight/obese asthma also associated with overweight/obesity among non-asthmatics. Beta-nerve growth factor (BetaNGF), interleukin 10 (IL-10), and matrix metalloproteinase 10 (MMP10) were associated only with lean asthma while C-C motif chemokine 20 (CCL20), fibroblast growth factor 19 (FGF19), interleukin 5 (IL-5), leukemia inhibitory factor (LIF), tumor necrosis factor ligand superfamily member 9 (TNFRSF9), and urokinase-type plasminogen activator (uPA) were associated only with overweight/obese asthma. Overweight/obesity modified the association between asthma and 3 of the proteins: fibroblast growth factor 21 (FGF21), interleukin 4 (IL-4), and urokinase-type plasminogen activator (uPA). In the overweight/obese group, interleukin-6 (IL-6) was associated with non-allergic asthma but not allergic asthma. CONCLUSION: These data indicate distinct plasma protein phenotypes in lean and overweight/obese asthmatics which, in turn, can impact upon therapeutic approaches.

19.
PLoS One ; 16(9): e0257396, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34550981

RESUMEN

Leukotrienes play a central pathophysiological role in both paediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. In this study we tested the role of the LTA4H regulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically diverse populations. We identified and genotyped 3,594 asthma patients treated with montelukast (2,514 late-onset and 1,080 early-onset) from seven cohorts (UKBiobank, GoSHARE, BREATHE, Tayside RCT, PAGES, GALA II and SAGE). Individuals under montelukast treatment experiencing at least one exacerbation in a 12-month period were compared against individuals with no exacerbation, using logistic regression for each cohort and meta-analysis. While no significant association was found with European late-onset subjects, a meta-analysis of 523 early-onset individuals from European ancestry demonstrated the odds of experiencing asthma exacerbations by carriers of at least one G allele, despite montelukast treatment, were increased (odds-ratio = 2.92, 95%confidence interval (CI): 1.04-8.18, I2 = 62%, p = 0.0412) compared to those in the AA group. When meta-analysing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR = 1.60, 95% CI: 0.61-4.19, I2 = 85%, p = 0.342). Our study demonstrates that genetic variation in LTA4H, together with timing of asthma onset, may contribute to variability in montelukast response. European individuals with early-onset (≤18y) carrying at least one copy of rs2660845 have increased odd of exacerbation under montelukast treatment, presumably due to the up-regulation of LTA4H activity. These findings support a precision medicine approach for the treatment of asthma with montelukast.


Asunto(s)
Acetatos/uso terapéutico , Asma/tratamiento farmacológico , Ciclopropanos/uso terapéutico , Epóxido Hidrolasas/genética , Farmacogenética , Quinolinas/uso terapéutico , Sulfuros/uso terapéutico , Adolescente , Adulto , Edad de Inicio , Alelos , Antiasmáticos/uso terapéutico , Asma/fisiopatología , Niño , Preescolar , Estudios Transversales , Europa (Continente) , Femenino , Genotipo , Hospitalización , Humanos , Antagonistas de Leucotrieno/uso terapéutico , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Análisis de Regresión , Riesgo , Adulto Joven
20.
J Pers Med ; 11(8)2021 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-34442380

RESUMEN

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.

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