European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Genomics of Treatable Traits in Asthma.

The astounding number of genetic variants revealed in the 15 years of genome-wide association studies of asthma has not kept pace with the goals of translational genomics. Moving asthma diagnosis from a nonspecific umbrella term to specific phenotypes/endotypes and related traits may provide insights into features that may be prevented or alleviated by therapeutical intervention. This review provides an overview of the different asthma endotypes and phenotypes and the genomic findings from asthma studies using patient stratification strategies and asthma-related traits. Asthma genomic research for treatable traits has uncovered novel and previously reported asthma loci, primarily through studies in Europeans. Novel genomic findings for asthma phenotypes and related traits may arise from multi-trait and specific phenotyping strategies in diverse populations.

Human genetics influences microbiome composition involved in asthma exacerbations despite inhaled corticosteroid treatment.

BACKGROUND: The upper-airway microbiome is involved in asthma exacerbations despite inhaled corticosteroid (ICS) treatment. Although human genetics regulates microbiome composition, its influence on asthma-related airway bacteria remains unknown. OBJECTIVE: We sought to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response. METHODS: Saliva, nasal, and pharyngeal samples from 257 European patients with asthma were analyzed. The association of 6,296,951 genetic variants with exacerbation-related microbiome traits despite ICS treatment was tested through microbiome genome-wide association studies. Variants with 1 × 10-4 

The upper-airway microbiome as a biomarker of asthma exacerbations despite inhaled corticosteroid treatment.

BACKGROUND: The response to inhaled corticosteroids (ICS) in asthma is affected by the interplay of several factors. Among these, the role of the upper-airway microbiome has been scarcely investigated. We aimed to evaluate the association between the salivary, pharyngeal, and nasal microbiome with asthma exacerbations despite receipt of ICS. METHODS: Samples from 250 asthma patients from the Genomics and Metagenomics of Asthma Severity (GEMAS) study treated with ICS were analyzed. Control/case subjects were defined by the absence/presence of asthma exacerbations in the past 6 months despite being treated with ICS. The bacterial microbiota was profiled by sequencing the V3-V4 region of the 16S rRNA gene. Differences between groups were assessed by PERMANOVA and regression models adjusted for potential confounders. A false discovery rate (FDR) of 5% was used to correct for multiple comparisons. Classification models of asthma exacerbations despite ICS treatment were built with machine learning approaches based on clinical, genetic, and microbiome data. RESULTS: In nasal and saliva samples, case subjects had lower bacterial diversity (Richness, Shannon, and Faith indices) than control subjects (.007 ≤ P ≤ .037). Asthma exacerbations accounted for 8% to 9% of the interindividual variation of the salivary and nasal microbiomes (.003 ≤ P ≤ .046). Three, 4, and 11 bacterial genera from the salivary, pharyngeal, and nasal microbiomes were differentially abundant between groups (4.09 × 10-12 ≤ FDR ≤ 0.047). Integrating clinical, genetic, and microbiome data showed good discrimination for the development of asthma exacerbations despite receipt of ICS (AUCtraining: 0.82 and AUCvalidation: 0.77). CONCLUSION: The diversity and composition of the upper-airway microbiome are associated with asthma exacerbations despite ICS treatment. The salivary microbiome has a potential application as a biomarker of asthma exacerbations despite receipt of ICS.

Multi-ancestry genome-wide association study of asthma exacerbations.

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.

Role of Sex on the Genetic Susceptibility to Childhood Asthma in Latinos and African Americans.

Asthma is a respiratory disease whose prevalence changes throughout the lifespan and differs by sex, being more prevalent in males during childhood and in females after puberty. In this study, we assessed the influence of sex on the genetic susceptibility to childhood asthma in admixed populations. Sex-interaction and sex-stratified genome-wide association studies (GWAS) were performed in 4291 Latinos and 1730 African Americans separately, and results were meta-analyzed. Genome-wide (p ≤ 9.35 × 10-8) and suggestive (p ≤ 1.87 × 10-6) population-specific significance thresholds were calculated based on 1000 Genomes Project data. Additionally, protein quantitative trait locus (pQTL) information was gathered for the suggestively associated variants, and enrichment analyses of the proteins identified were carried out. Four independent loci showed interaction with sex at a suggestive level. The stratified GWAS highlighted the 17q12-21 asthma locus as a contributor to asthma susceptibility in both sexes but reached genome-wide significance only in females (p-females < 9.2 × 10-8; p-males < 1.25 × 10-2). Conversely, genetic variants upstream of ligand-dependent nuclear receptor corepressor-like gene (LCORL), previously involved in height determination and spermatogenesis, were associated with asthma only in males (minimum p = 5.31 × 10-8 for rs4593128). Enrichment analyses revealed an overrepresentation of processes related to the immune system and highlighted differences between sexes. In conclusion, we identified sex-specific polymorphisms that could contribute to the differences in the prevalence of childhood asthma between males and females.

LTA4H rs2660845 association with montelukast response in early and late-onset asthma.

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.

Genome-wide association study reveals a novel locus for asthma with severe exacerbations in diverse populations.

BACKGROUND: Severe asthma exacerbations are a major cause of asthma morbidity and increased healthcare costs. Several studies have shown racial and ethnic differences in asthma exacerbation rates. We aimed to identify genetic variants associated with severe exacerbations in two high-risk populations for asthma. METHODS: A genome-wide association study of asthma in children and youth with severe exacerbations was performed in 1283 exacerbators and 2027 controls without asthma of Latino ancestry. Independent suggestive variants (P ≤ 5 × 10-6 ) were selected for replication in 448 African Americans exacerbators and 595 controls. Case-only analyses were performed comparing the exacerbators with additional 898 Latinos and 524 African Americans asthma patients without exacerbations, while adjusting by treatment category as a proxy of asthma severity. We analyzed the functionality of associated variants with in silico methods and by correlating genotypes with methylation levels in whole blood in a subset of 473 Latinos. RESULTS: We identified two genome-wide significant associations for susceptibility to asthma with severe exacerbations, including a novel locus located at chromosome 2p21 (rs4952375, odds ratio = 1.39, P = 3.8 × 10-8 ), which was also associated with asthma exacerbations in a case-only analysis (odds ratio = 1.25, P = 1.95 × 10-3 ). This polymorphism is an expression quantitative trait locus of the long intergenic non-protein coding RNA 1913 (LINC01913) in lung tissues (P = 1.3 × 10-7 ) and influences methylation levels of the protein kinase domain-containing cytoplasmic (PKDCC) gene in whole-blood cells (P = 9.8 × 10-5 ). CONCLUSION: We identified a novel susceptibility locus for severe asthma exacerbations in Hispanic/Latino and African American youths with functional effects in gene expression and methylation status of neighboring genes.

The Genomics and Metagenomics of Asthma Severity (GEMAS) Study: Rationale and Design.

Asthma exacerbations are a major contributor to the global disease burden, but no significant predictive biomarkers are known. The Genomics and Metagenomics of Asthma Severity (GEMAS) study aims to assess the role of genomics and the microbiome in severe asthma exacerbations. Here, we present the design of GEMAS and the characteristics of patients recruited from March 2018 to March 2020. Different biological samples and demographic and clinical variables were collected from asthma patients recruited by allergy and pulmonary medicine units in several hospitals from Spain. Cases and controls were defined by the presence/absence of severe asthma exacerbations in the past year (oral corticosteroid use, emergency room visits, and/or asthma-related hospitalizations). A total of 137 cases and 120 controls were recruited. After stratifying by recruitment location (i.e., Canary Islands and Basque Country), cases and controls did not differ for most demographic and clinical variables (p > 0.05). However, cases showed a higher proportion of characteristics inherent to asthma exacerbations (impaired lung function, severe disease, uncontrolled asthma, gastroesophageal reflux, and use of asthma medications) compared to controls (p < 0.05). Similar results were found after stratification by recruitment unit. Thereby, asthma patients enrolled in GEMAS are balanced for potential confounders and have clinical characteristics that support the phenotype definition. GEMAS will improve the knowledge of potential biomarkers of asthma exacerbations.

Pharmacogenetics of Pediatric Asthma: Current Perspectives.

Asthma is a chronic respiratory disease that affects 339 million people worldwide and has a considerable impact on the pediatric population. Asthma symptoms can be controlled by pharmacological treatment. However, some patients do not respond to therapy and continue suffering from symptoms, which impair the quality of life of patients and limit their daily activity. Genetic variation has been shown to have a role in treatment response. The aim of this review is to update the main findings described in pharmacogenetic studies of pediatric asthma published from January 1, 2018 to December 31, 2019. During this period, the response to short-acting beta-agonists and inhaled corticosteroids in childhood asthma has been evaluated by eleven candidate-gene studies, one meta-analysis of a candidate gene, and six pharmacogenomic studies. The findings have allowed validating the association of genes previously related to asthma treatment response (ADRB2, GSDMB, FCER2, VEGFA, SPAT2SL, ASB3, and COL2A1), and identifying novel associations (PRKG1, DNAH5, IL1RL1, CRISPLD2, MMP9, APOBEC3B-APOBEC3C, EDDM3B, and BBS9). However, some results are not consistent across studies, highlighting the need to conduct larger studies in diverse populations with more homogeneous definitions of treatment response. Once stronger evidence was established, genetic variants will have the potential to be applied in clinical practice as biomarkers of treatment response enhancing asthma management and improving the quality of life of asthma patients.

Bacterial salivary microbiome associates with asthma among african american children and young adults.

Several studies have shown that the airways of asthma patients contain higher diversity of bacteria and are enriched in pathogenic species. However, sampling the airways in children is challenging. Here we aimed to identify differences in the salivary bacterial composition between African Americans children with and without asthma. Saliva samples from 57 asthma cases and 57 healthy controls were analyzed by means of 16S ribosomal RNA amplicon profiling. Measurements of bacterial diversity and genus relative abundance were compared between cases and controls using the nonparametric Wilcoxon test and multivariate regression models. A total of five phyla and a mean of 56 genera were identified. Among them, 15 genera had a relative abundance greater than 1%, being Prevotella, Haemophilus, Streptococcus, and Veillonella the most abundant genera. Differences between cases and controls were found in terms of diversity, as well as in relative abundance for Streptococcus genus (13.0% in cases vs 18.3% in controls; P = .003) and Veillonella genus (11.1% in cases vs 8.0% in controls; P = .002). These differences remained significant after correction for multiple comparisons and when potential confounders were taken into account in logistic regression models. In conclusion, we identified changes in the salivary microbiota associated with asthma among African Americans.