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Background: Asthma exacerbations reflect disease severity, affect morbidity and mortality, and may lead to declining lung function. Inflammatory endotypes (e.g. T2-high (eosinophilic)) may play a key role in asthma exacerbations. We aimed to assess whether genetic susceptibility underlies asthma exacerbation risk and additionally tested for an interaction between genetic variants and eosinophilia on exacerbation risk. Methods: UK Biobank data were used to perform a genome-wide association study of individuals with asthma and at least one exacerbation compared to individuals with asthma and no history of exacerbations. Individuals with asthma were identified using self-reported data, hospitalisation data and general practitioner records. Exacerbations were identified as either asthma-related hospitalisation, general practitioner record of asthma exacerbation or an oral corticosteroid burst prescription. A logistic regression model adjusted for age, sex, smoking status and genetic ancestry via principal components was used to assess the association between genetic variants and asthma exacerbations. We sought replication for suggestive associations (p<5×10-6) in the GERA cohort. Results: In the UK Biobank, we identified 11 604 cases and 37 890 controls. While no variants reached genome-wide significance (p<5×10-8) in the primary analysis, 116 signals were suggestively significant (p<5×10-6). In GERA, two single nucleotide polymorphisms (rs34643691 and rs149721630) replicated (p<0.05), representing signals near the NTRK3 and ABCA13 genes. Conclusions: Our study has identified reproducible associations with asthma exacerbations in the UK Biobank and GERA cohorts. Confirmation of these findings in different asthma subphenotypes in diverse ancestries and functional investigation will be required to understand their mechanisms of action and potentially inform therapeutic development.
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BACKGROUND: The prevalence and clinical profile of asthma with airflow obstruction (AO) remain uncertain. We aimed to phenotype AO in population- and clinic-based cohorts. METHODS: This cross-sectional multicohort study included adults ≥50 years from nine CADSET cohorts with spirometry data (N=69 789). AO was defined as ever diagnosed asthma with pre-BD or post-BD FEV1/FVC <0.7 in population-based and clinic-based cohorts, respectively. Clinical characteristics and comorbidities of AO were compared with asthma without airflow obstruction (asthma-only) and chronic obstructive pulmonary disease (COPD) without asthma history (COPD-only). ORs for comorbidities adjusted for age, sex, smoking status and body mass index (BMI) were meta-analysed using a random effects model. RESULTS: The prevalence of AO was 2.1% (95% CI 2.0% to 2.2%) in population-based, 21.1% (95% CI 18.6% to 23.8%) in asthma-based and 16.9% (95% CI 15.8% to 17.9%) in COPD-based cohorts. AO patients had more often clinically relevant dyspnoea (modified Medical Research Council score ≥2) than asthma-only (+14.4 and +14.7 percentage points) and COPD-only (+24.0 and +5.0 percentage points) in population-based and clinic-based cohorts, respectively. AO patients had more often elevated blood eosinophil counts (>300 cells/µL), although only significant in population-based cohorts. Compared with asthma-only, AO patients were more often men, current smokers, with a lower BMI, had less often obesity and had more often chronic bronchitis. Compared with COPD-only, AO patients were younger, less often current smokers and had less pack-years. In the general population, AO patients had a higher risk of coronary artery disease than asthma-only and COPD-only (OR=2.09 (95% CI 1.26 to 3.47) and OR=1.89 (95% CI 1.10 to 3.24), respectively) and of depression (OR=1.41 (95% CI 1.19 to 1.67)), osteoporosis (OR=2.30 (95% CI 1.43 to 3.72)) and gastro-oesophageal reflux disease (OR=1.68 (95% CI 1.06 to 2.68)) than COPD-only, independent of age, sex, smoking status and BMI. CONCLUSIONS: AO is a relatively prevalent respiratory phenotype associated with more dyspnoea and a higher risk of coronary artery disease and elevated blood eosinophil counts in the general population compared with both asthma-only and COPD-only.
Subject(s)
Asthma , Coronary Artery Disease , Pulmonary Disease, Chronic Obstructive , Male , Humans , Cross-Sectional Studies , Asthma/epidemiology , Pulmonary Disease, Chronic Obstructive/epidemiology , DyspneaABSTRACT
The China Kadoorie Biobank (CKB) is a population-based prospective cohort of >512,000 adults recruited from 2004 to 2008 from 10 geographically diverse regions across China. Detailed data from questionnaires and physical measurements were collected at baseline, with additional measurements at three resurveys involving â¼5% of surviving participants. Analyses of genome-wide genotyping, for >100,000 participants using custom-designed Axiom arrays, reveal extensive relatedness, recent consanguinity, and signatures reflecting large-scale population movements from recent Chinese history. Systematic genome-wide association studies of incident disease, captured through electronic linkage to death and disease registries and to the national health insurance system, replicate established disease loci and identify 14 novel disease associations. Together with studies of candidate drug targets and disease risk factors and contributions to international genetics consortia, these demonstrate the breadth, depth, and quality of the CKB data. Ongoing high-throughput omics assays of collected biosamples and planned whole-genome sequencing will further enhance the scientific value of this biobank.
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SUMMARY: DeepPheWAS is an R package for phenome-wide association studies that creates clinically curated composite phenotypes and integrates quantitative phenotypes from primary care data, longitudinal trajectories of quantitative measures, disease progression and drug response phenotypes. Tools are provided for efficient analysis of association with any genetic input, under any genetic model, with optional sex-stratified analysis, and for developing novel phenotypes. AVAILABILITY AND IMPLEMENTATION: The DeepPheWAS R package is freely available under GNU general public licence v3.0 from at https://github.com/Richard-Packer/DeepPheWAS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
Phenomics , Software , PhenotypeABSTRACT
INTRODUCTION: Older adults have the greatest burden of asthma and poorest outcomes. The pharmacogenetics of inhaled corticosteroid (ICS) treatment response is not well studied in older adults. METHODS: A genome-wide association study of ICS response was performed in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) by fitting Cox proportional hazards regression models, followed by validation in the Mass General Brigham (MGB) Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid (OCS) bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. A fixed-effect meta-analysis was performed for each outcome. The validated single-nucleotide polymorphisms (SNPs) were functionally annotated to standard databases. RESULTS: In 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six near PTCHD4 validated across all cohorts and met genome-wide significance on meta-analysis for the OCS burst outcome. In 4541 subjects in GERA and 505 subjects in MGB Biobank, 152 SNPs with p<5 × 10-5 were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci for CPED1, CRADD and DST for the OCS burst outcome and GM2A, SNW1, CACNA1C, DPH1, and RPS10 for the asthma-related exacerbation outcome. CONCLUSIONS: Multiple novel SNPs associated with ICS response were identified in older adult asthmatics. Several SNPs annotated to genes previously associated with asthma and other airway or allergic diseases, including PTCHD4.
Subject(s)
Anti-Asthmatic Agents , Asthma , Humans , Aged , Genome-Wide Association Study , Administration, Inhalation , Asthma/drug therapy , Asthma/genetics , Asthma/epidemiology , Adrenal Cortex Hormones/therapeutic useABSTRACT
BACKGROUND: Personalized medicine is an emerging field, aiming to improve the safety and efficacy of pharmacotherapy. The field's implementation in clinical care is steadily increasing. Pharmacogenomics are one example of personalized approaches in the clinic and direct-to-consumer (DTC) pharmacogenomic tests have become publicly available. We aimed to assess public opinion on pharmacogenomic research and testing to foster integration within Belgian health care. METHODS: A cross-sectional survey was created and disseminated online, focusing on the citizen perspective. Participants' willingness to engage in pharmacogenomic research was the primary outcome. In addition, their awareness, understanding, expectations and overall acceptance towards pharmacogenomic testing was investigated. RESULTS: A total of 156 participants (54.5% aged between 18 and 30 years, 45.5% > 30 years; 73.1% females) completed the survey. Half ever experienced side effects (46.2%) and treatment failure (52.6%). Up to 45.5% (n = 71) were willing to participate in pharmacogenomics research, and the majority (78.8%) were convinced that pharmacogenomic tests could help doctors to prescribe them the right medications. Additionally, 76.3% (n = 118) supported a partial reimbursement of pharmacogenomics tests. A minority (5.1%, n = 8) of participants showed interest in DTC tests, and 15.4% (n = 24) expressed privacy concerns regarding pharmacogenomics testing. Participants preferred their healthcare professionals' to perform the test and access their data, but refused commercial providers. CONCLUSION: Overall, participants showed a positive attitude towards precision medicine and pharmacogenomics research. Our findings may help guiding future pharmacogenomic implementation initiatives to optimize drug use by using pharmacogenomic information integrated within health care.
Subject(s)
Pharmacogenetics , Precision Medicine , Adolescent , Adult , Attitude , Cross-Sectional Studies , Female , Humans , Male , Public Opinion , Young AdultABSTRACT
BACKGROUND: Inhaled corticosteroids (ICS) are a cornerstone of asthma treatment. However, their efficacy is characterized by wide variability in individual responses. OBJECTIVE: We investigated the association between genetic variants and risk of exacerbations in adults with asthma and how this association is affected by ICS treatment. METHODS: We investigated the pharmacogenetic effect of 10 single nucleotide polymorphisms (SNPs) selected from the literature, including SNPs previously associated with response to ICS (assessed by change in lung function or exacerbations) and novel asthma risk alleles involved in inflammatory pathways, within all adults with asthma from the Dutch population-based Rotterdam study with replication in the American GERA cohort. The interaction effects of the SNPs with ICS on the incidence of asthma exacerbations were assessed using hurdle models adjusting for age, sex, BMI, smoking and treatment step according to the GINA guidelines. Haplotype analyses were also conducted for the SNPs located on the same chromosome. RESULTS: rs242941 (CRHR1) homozygotes for the minor allele (A) showed a significant, replicated increased risk for frequent exacerbations (RR = 6.11, P < 0.005). In contrast, rs1134481 T allele within TBXT (chromosome 6, member of a family associated with embryonic lung development) showed better response with ICS. rs37973 G allele (GLCCI1) showed a significantly poorer response on ICS within the discovery cohort, which was also significant but in the opposite direction in the replication cohort. CONCLUSION: rs242941 in CRHR1 was associated with poor ICS response. Conversely, TBXT variants were associated with improved ICS response. These associations may reveal specific endotypes, potentially allowing prediction of exacerbation risk and ICS response.
Subject(s)
Anti-Asthmatic Agents , Asthma , Administration, Inhalation , Adrenal Cortex Hormones/adverse effects , Adult , Anti-Asthmatic Agents/therapeutic use , Asthma/diagnosis , Asthma/drug therapy , Asthma/genetics , Humans , PharmacogeneticsABSTRACT
INTRODUCTION: Novel treatments target eosinophilic inflammation in type 2 asthma. We aimed to evaluate and meta-analyze the efficacy of monoclonal antibodies to reduce exacerbation rate. EVIDENCE ACQUISITION: PubMed and Embase were searched for phase II and phase III randomized clinical trials with monoclonal antibodies targeting key mediators of type 2-associated asthma between 2019 and 2021 to update our previous meta-analysis covering studies published from 2005 to 2018. Five-hundred and sixty six publications have been identified, of which six recent trials (on top of 30 previously identified) involving mepolizumab, benralizumab, reslizumab and dupilumab met our inclusion criteria. As no head-to-head trials were retrieved from literature, we performed an arm-based network meta-analysis including a total of 19 RCTs to compare effects on exacerbation rate between the different treatments. EVIDENCE SYNTHESIS: Benralizumab significantly reduced the risk of exacerbations compared to the pooled placebo in our network meta-analysis (median effect difference: -0.520, 95% CI [-1.010- -0.048]). No biologic showed superiority over the others in indirect comparisons. Large reductions in exacerbation rates were observed compared to placebo, though only benralizumab was sufficiently powered (N.=2564) to demonstrate significantly decreased exacerbation rates both in the overall population and in the subgroup analysis of IL-5 acting agents compared to placebo. CONCLUSIONS: Monoclonal antibodies have proven their benefit to reduce exacerbation rates in severe persistent eosinophilic asthma in the published trials. No biological showed superiority over the others emphasizing the need for clearly defined endotypes indicating those patients who will optimally benefit for each treatment.
Subject(s)
Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Network Meta-Analysis , Antibodies, Monoclonal, Humanized/therapeutic use , Bias , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Humans , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: Epigenetics may play an important role in the pathogenesis of lung diseases. However, little is known about the epigenetic factors that influence impaired gas exchange at the lung. AIM: To identify the epigenetic signatures of the diffusing capacity of the lung measured by carbon monoxide uptake (the diffusing capacity of the lung for carbon monoxide (D LCO)). METHODS: An epigenome-wide association study (EWAS) was performed on diffusing capacity, measured by carbon monoxide uptake (D LCO) and per alveolar volume (V A) (as D LCO/V A), using the single-breath technique in 2674 individuals from two population-based cohort studies. These were the Rotterdam Study (RS, the "discovery panel") and the Framingham Heart Study (FHS, the "replication panel"). We assessed the clinical relevance of our findings by investigating the identified sites in whole blood and by lung tissue specific gene expression. RESULTS: We identified and replicated two CpG sites (cg05575921 and cg05951221) that were significantly associated with D LCO/V A and one (cg05575921) suggestively associated with D LCO. Furthermore, we found a positive association between aryl hydrocarbon receptor repressor (AHRR) gene (cg05575921) hypomethylation and gene expression of exocyst complex component 3 (EXOC3) in whole blood. We confirmed that the expression of EXOC3 in lung tissue is positively associated with D LCO/V A and D LCO. CONCLUSIONS: We report on epigenome-wide associations with diffusing capacity in the general population. Our results suggest EXOC3 to be an excellent candidate, through which smoking-induced hypomethylation of AHRR might affect pulmonary gas exchange.
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Over the past decade, pharmacogenetics (PGx) became an essential tool for personalized medicine although its clinical implementation is still limited. We aimed to assess the current level of knowledge, applications, and expectations of Flemish pharmacists and physicians towards PGx and determine the factors that influence healthcare professionals' knowledge of PGx, aiming to guide future implementation initiatives. A web-based cross-sectional survey was conducted from 8 March 2019 to 8 April 2019, targeting pharmacists, physicians, and trainees of both professions. Ten questions were used to assess the participants' knowledge about PGx. Multivariable linear regression was used to assess the association of profession, experience, practice setting, and prior education with the level of PGx knowledge. In total, 201 Flemish healthcare providers participated, including 100 pharmacists, 73 physicians, and 28 trainees. The majority (78%) of participants were unfamiliar with the basic principles of PGx and its application in clinical practice. The mean percentage of correct answers achieved for the knowledge assessment questions was 34%. Only 9% had counseled patients, while 8% assisted other healthcare professionals on PGx tests the past year. Participants' PGx knowledge was significantly affected by their profession, practice setting, and level of prior education independent of years of experience. These findings provide insight into factors affecting the knowledge of PGx and the current level of PGx implementation in Flemish clinical practice. This may form a basis for developing educational initiatives to enhance the clinical application of PGx in Flanders.
Subject(s)
Pharmacists/psychology , Pharmacogenetics/trends , Physicians/psychology , Precision Medicine/trends , Attitude of Health Personnel , Cross-Sectional Studies , Female , Humans , Male , Pharmacists/standards , Physicians/standards , Surveys and QuestionnairesABSTRACT
Since novel treatments to target eosinophilic inflammation in Type 2 asthma are emerging, we aimed to evaluate and meta-analyze the efficacy of monoclonal antibodies to reduce exacerbation rate. PubMed and Web of Science were searched for phase II and phase III randomized clinical trials with monoclonal antibodies targeting key mediators of type 2-associated asthma. Thirty trials were selected involving biologics that target the IL-5 pathway, IL-13, the common IL-4 and IL-13 receptor, IL-9, IL-2 and TSLP. As no head-to-head trials were retrieved from literature, we performed an arm-based network meta-analysis to compare effects on exacerbation rate between the different treatments.Mepolizumab, reslizumab and benralizumab significantly reduced the risk of exacerbations compared to placebo (by 47-52%, 50-60%, and 28-51% respectively). Reslizumab and benralizumab also improved lung function. Dupilumab and tezepelumab improved lung function in frequent exacerbators. Lebrikizumab had no significant effect on the number of exacerbations, symptom control or health-related quality of life. Tralokinumab improved lung function compared to placebo. Network meta-analysis of all treatment and placebo arms, showed no superiority of one biologic over the others. Large reductions in exacerbation rates were observed compared to placebo, though only benralizumab was sufficiently powered (n = 2051) to demonstrate significantly decreased exacerbation rates in the subgroup analysis of IL-5 acting agents compared to placebo.Monoclonal antibodies such as mepolizumab, reslizumab and benralizumab have proven their benefit to reduce exacerbation rates in severe persistent eosinophilic asthma in the published trials. However, no statistically significant superiority was observed of one biologic over the other in the network meta-analysis. More studies with direct head to head comparisons and better defined endotypes are required.
Subject(s)
Anti-Asthmatic Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Asthma/drug therapy , Anti-Asthmatic Agents/blood , Antibodies, Monoclonal/blood , Asthma/blood , Asthma/diagnosis , Humans , Network Meta-Analysis , Randomized Controlled Trials as Topic/methodsABSTRACT
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.
Subject(s)
Asthma/genetics , Asthma/immunology , CpG Islands/immunology , DNA Methylation/immunology , Epigenesis, Genetic/immunology , Epigenome/immunology , Genome-Wide Association Study , HumansABSTRACT
OBJECTIVE: Nonsyndromic orofacial cleft (NSOFC) including cleft lip with or without cleft palate (CL±P) and cleft palate (CP) are multifactorial developmental disorders with both genetic and environmental etiological factors. In this study we investigated the association between CL±P and CP, and two polymorphisms previously determined using genome-wide association studies, as well as the association between consanguinity and CL±P and CP. METHODS: DNA was extracted from saliva specimens from 171 triads consisting of affected individuals and their parents, as well as 189 control triads (matched for age, gender, and location) that were recruited from 11 referral hospitals in Saudi Arabia. Two polymorphisms, rs4752028 and rs7078160, located in the VAX1 gene were genotyped using real-time polymerase chain reaction. A transmission disequilibrium test was carried out using the Family-Based Association Test and PLINK (genetic tool-set) to measure the parent-of-origin effect. RESULTS: Significant differences were found between affected individuals and the control group. In the case of the rs4752028 risk allele in cleft, the phenotypes were: CL±P (fathers: odds ratio [OR] 2.16 [95% CI 1.38-3.4]; mothers: OR 2.39 [95% CI 1.53-3.71]; and infants: OR 2.77 [95% CI 1.77-4.34]) and CP (fathers: OR 2.24 [95% CI 1.15-4.36] and infants: OR 2.43 [95% CI 1.25-4.7]). For CL±P and the rs7078160 risk allele, the phenotypes were: (fathers: OR 1.7 [95% CI 1.05-2.86]; mothers: OR 2.43 [95% CI 1.49-3.97]; and infants: OR 2.34 [95% CI 1.44-3.81]). In terms of consanguinity, we found significant association between consanguinity and the rs4752028 polymorphism minor allele among CL±P compared with controls (p = 0.001). CONCLUSION: This is the first study to find a relationship between these two loci on 10q25 (rs4752028 and rs7078160) and NSOFC in a population with high levels of consanguinity.