Lessons from ten years of genome‐wide association studies of asthma

Vicente, Cristina T; Revez, Joana A.; Ferreira, Manuel

doi:10.1038/cti.2017.54

Cited by 101 publications

(118 citation statements)

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“…In parallel, we found that the rs2228145:C allele was associated with a 1.09-fold higher risk of asthma in individuals of European descent, 66 an observation that has since been replicated in the UK Biobank study. 64,67 A similar association (odds ratio [OR] = 1.08) was also reported for atopic dermatitis (AD or eczema), 68 with a stronger effect (OR = 1.22) observed for the persistent form of AD. 69 Recently, we showed that rs2228145:C occurs at the same frequency in cases that suffer from asthma, hay fever or AD, therefore confirming its effect on the risk of multiple allergic diseases.…”

Section: Introductionsupporting

confidence: 53%

Effects of interleukin‐6 receptor blockade on allergen‐induced airway responses in mild asthmatics

et al. 2019

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Background Interleukin (IL)‐6 signalling has been implicated in allergic asthma by animal, genetic association and clinical studies. In this study, we tested the hypothesis that tocilizumab (TCZ), a human monoclonal antibody that blocks IL‐6 signalling, can prevent the development of allergen‐induced bronchoconstriction in humans. Methods We performed a randomised, double‐blind, placebo‐controlled study, with eligible participants completing two allergen inhalation challenge tests, conducted before and after treatment with a single dose of TCZ or placebo. The primary efficacy endpoint was the magnitude of the late asthmatic response recorded between 3 and 7 after allergen challenge. The secondary efficacy endpoint was the early asthmatic response, measured 20 min to 2 h after allergen challenge. Results A total of 66 patients enrolled between September 2014 and August 2017, when the trial was stopped for futility based on results from an interim analysis. Eleven patients fulfilled all eligibility criteria assessed at baseline and were subsequently randomised to the TCZ ( n = 6) or placebo ( n = 5) groups. Both the primary and secondary efficacy endpoints were not significantly different between the two groups. Five patients reported adverse events (AEs), three in the TCZ group (11 AEs) and two in the placebo group (four AEs). Only one AE was TCZ‐related (mild neutropenia), and there were no serious AEs. Significant treatment effects were observed for serum levels of C‐reactive protein, IL‐6 and soluble IL‐6R levels. Conclusion In a small proof‐of‐concept clinical trial, we found no evidence that a single dose of tocilizumab was able to prevent allergen‐induced bronchoconstriction. (Trial registered in the Australian New Zealand Clinical Trials Registry, number ACTRN12614000123640).

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Section: Introductionsupporting

confidence: 53%

Effects of interleukin‐6 receptor blockade on allergen‐induced airway responses in mild asthmatics

et al. 2019

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“…variants associated with childhood asthma in large-scale GWA studies only account for a low fraction of variance in asthma severity, endotypes, heritability and clinical response to therapy. [5][6][7][8] Environmental exposures, such as tobacco smoke exposure during pregnancy, lack of breastfeeding and air pollutants that affect lung development and risk of asthma may alter gene activity and expression without changing underlying DNA sequence, referred to by the term epigenetics. [8][9][10] The genetic make-up of an individual and its interaction with the environment can both affect epigenetic mechanisms.…”

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confidence: 99%

Epigenome‐wide association studies in asthma: A systematic review

Edris

Dekker

Melén

et al. 2019

Clin Experimental Allergy

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Objective Asthma is a common chronic respiratory airway disease influenced by environmental factors and possibly their interaction with the human genome causing epigenetic changes. Epigenome‐wide association studies (EWAS) have mainly investigated DNA methylation and its association with disease or traits, exposure factors or gene expression. This systematic review aimed to identify all EWAS assessing differentially methylated sites associated with asthma in humans. Design Structured systematic literature search following PRISMA guidelines, Newcastle‐Ottawa Scale (NOS) for cohort studies was used for bias assessment. Data Sources We searched PubMed and Embase databases from 2005 to 2019. Eligibility Criteria Epigenome‐wide association studies testing association between differential methylation and asthma in humans. Results Overall, we identified 16 EWAS studies complying with our search criteria. Twelve studies were conducted on children, and 10 were conducted on sample sizes <150 subjects. Four hundred and nineteen CpGs were reported in children studies after correction for multiple testing. In the adult studies, thousands of differentially methylated sites were identified. Differential methylation in inflammatory‐related genes correlated with higher levels of gene expressions of inflammatory modulators in asthma. Differentially methylated genes associated with asthma included SMAD3, SERPINC1, PROK1, IL13, RUNX3 and TIGIT. Forty‐one CpGs were replicated at least once in blood samples, and 28 CpGs were replicated in nasal samples. Conclusion Although many differentially methylated CpGs in genes known to be involved in asthma have been identified in EWAS to date, we conclude that further studies of larger sample sizes and analyses of differential methylation between different phenotypes are needed in order to comprehensively evaluate the role of epigenetic factors in the pathophysiology and heterogeneity of asthma, and the potential clinical utility to predict or classify patients with asthma.

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“…Variants identified through GWAS only account for a small percentage of the heritability with the known lung function signals accounting for 9.6%, 6.4% and 14.3% of the heritability for FEV 1 , FVC and FEV 1 /FVC, respectively . In asthma, 2.5% of heritability is estimated to be due to SNP discovered through GWAS . This missing heritability is often attributed to the limitations of GWAS and it is a fact that GWAS only detect common variants and ignore other types of genomic variation such as rare variants and copy number variations.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, SNP spanning IL1RL1 , the IL‐33 receptor, are associated with childhood asthma, severe asthma and with a diagnosis of allergic rhinitis . For an excellent review of GWAS in asthma up until 2016, see the study by Vicente et al …”

Section: Methods For Studying Genetics Of Respiratory Diseasementioning

confidence: 99%

“…56,58,62,63 Interestingly, SNP spanning IL1RL1, the IL-33 receptor, are associated with childhood asthma, severe asthma and with a diagnosis of allergic rhinitis. 56,63,68 For an excellent review of GWAS in asthma up until 2016, see the study by Vicente et al 70 A 2017 study found a further four novel loci after a meta-analysis on 21 644 European American and African American individuals. 67 6p21.31, 9p21.2 and 10q21.3 were the loci identified in the European American population with TEK at the 9p21.2 locus of specific interest due to its known involvement in remodelling in the lung.…”

Section: Gwas In Asthmamentioning

confidence: 99%

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Genetic risk factors for the development of pulmonary disease identified by genome‐wide association

Hall

Sayers

2018

Respirology

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Chronic respiratory diseases are a major cause of morbidity and mortality. Asthma and chronic obstructive pulmonary disease (COPD) combined affect over 500 million people worldwide. While environmental factors are important in disease progression, asthma and COPD have long been known to be heritable with genetic components playing an important role in the risk of developing disease. Identification of genetic variation contributing to disease progression is important for a number of reasons including identification of risk alleles, understanding underlying disease mechanisms and development of novel therapies. Genome‐wide association studies (GWAS) have been successful in identifying many loci associated with lung function, COPD and asthma. In recent years, meta‐analyses and improved imputation have facilitated the growth of GWAS in terms of numbers of subjects and the number of single nucleotide polymorphisms (SNP) that can be interrogated. As a consequence, there has been a significant increase in the number of signals associated with asthma, COPD and lung function. SNP that have shown association with lung function reassuringly show a significant overlap with SNP associated with COPD giving a glimpse at pathways that may be involved in COPD mechanisms including genes in, for example, developmental pathways. In asthma, association signals are often in or near genes involved in both adaptive and innate immune response pathways, epithelial cell homeostasis and airway structural changes. The challenges now are translating these genetic signals into a new understanding of lung biology, understanding how variants impact health and disease and how they may provide opportunities for therapeutic intervention.

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Lessons from ten years of genome‐wide association studies of asthma

Cited by 101 publications

References 133 publications

Effects of interleukin‐6 receptor blockade on allergen‐induced airway responses in mild asthmatics

Effects of interleukin‐6 receptor blockade on allergen‐induced airway responses in mild asthmatics

Epigenome‐wide association studies in asthma: A systematic review

Genetic risk factors for the development of pulmonary disease identified by genome‐wide association

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