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- Herrera-Luis, E, et al.
(author)
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Admixture mapping of severe asthma exacerbations in Hispanic/Latino children and youth
- 2023
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In: Thorax. - : BMJ. - 1468-3296 .- 0040-6376. ; 78:3, s. 233-241
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Journal article (peer-reviewed)abstract
- In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations.ObjectiveWe sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles.MethodsWe performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases.ResultsGenomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 (C5orf46) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated withDPYSL3DNA methylation andSCGB3A2gene expression levels.ConclusionsAdmixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulatedDPYSL3andSCGB3A2.
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- Farzan, N, et al.
(author)
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Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium
- 2017
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In: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 18:10, s. 931-943
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Journal article (peer-reviewed)abstract
- 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.
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- Hernandez-Pacheco, N, et al.
(author)
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Genome-wide association study of asthma exacerbations despite inhaled corticosteroid use
- 2021
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In: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 57:5
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Journal article (peer-reviewed)abstract
- 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.MethodsA 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.Results10 independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10−6). Of those, one variant at theCACNA2D3-WNT5Alocus 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.ConclusionsThe intergenic region ofCACNA2D3andWNT5Awas 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.
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- Loth, Daan W, et al.
(author)
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Genome-wide association analysis identifies six new loci associated with forced vital capacity
- 2014
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46, s. 669-677
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Journal article (peer-reviewed)abstract
- Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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- Meier, H. E. M., et al.
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Ventilation of the Baltic Sea deep water: A brief review of present knowledge from observations and models
- 2006
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In: Oceanologia. - 0078-3234. ; 48, s. 133-164
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Journal article (peer-reviewed)abstract
- The ventilation of the Baltic Sea deep water is driven by either gale-forced barotropic or baroclinic salt water inflows. During the past two decades, the frequency of large barotropic inflows (mainly in winter) has decreased and the frequency of medium-intensity baroclinic inflows (observed in summer) has increased. As a result of entrainment of ambient oxygen-rich water, summer inflows are also important for the deep water ventilation. Recent process studies of salt water plumes suggest that the entrainment rates are generally smaller than those predicted by earlier entrainment models. In addition to the entrance area, the Slupsk Sill and the Slupsk Furrow are important locations for the transformation of water masses. Passing the Slupsk Furrow, both gravity-driven dense bottom flows and sub-surface cyclonic eddies, which are eroded laterally by thermohaline intrusions, ventilate the deep water of the eastern Gotland Basin. A recent study of the energy transfer from barotropic to baroclinic wave motion using a two-dimensional shallow water model suggests that about 30% of the energy needed below the halocline for deep water mixing is explained by the breaking of internal waves. In the deep water decade-long stagnation periods with decreasing oxygen and increasing hydrogen sulphide concentrations might be caused by anomalously large freshwater inflows and anomalously high mean zonal wind speeds. In different studies the typical response time scale of average salinity was estimated to be between approximately 20 and 30 years. The review summarizes recent research results and ends with a list of open questions and recommendations.
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- Turner, S, et al.
(author)
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Variants in genes coding for glutathione S-transferases and asthma outcomes in children
- 2018
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In: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 19:8, s. 707-713
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Journal article (peer-reviewed)abstract
- Our hypothesis was that children with mutations in genes coding for glutathione S-transferases (GST) have worse asthma outcomes compared with children with active type genotype. Data were collected in five populations. The rs1695 single nucleotide polymorphism (GSTP1) was determined in all cohorts (3692 children) and GSTM1 and GSTT1 null genotype were determined in three cohorts (2362 children). GSTT1 null (but not other genotypes) was associated with a minor increased risk for asthma attack and there were no significant associations between GST genotypes and asthma severity. Interactions between GST genotypes and SHS exposure or asthma severity with the study outcomes were nonsignificant. We find no convincing evidence that the GST genotypes studied are related to asthma outcomes.
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