<scp>HLA</scp>‐<scp>DQ</scp> strikes again: Genome‐wide association study further confirms <i><scp>HLA</scp>‐<scp>DQ</scp></i> in the diagnosis of asthma among adults

Lasky‐Su, Jessica; Himes, Blanca E.; Raby, Benjamin A.; Klanderman, Barbara J.; Sylvia, Jody S.; Lange, Christoph; Melén, Erik; Martínez, Fernando D.; Israel, Elliot; Gauderman, W. James; Gilliland, Frank D.; Sleiman, Patrick; Hákonarson, Hákon; Celedón, Juan C.; Soto-Quirós, Manuel E.; Avila, Lydiana; Lima, John J.; Irvin, Charles G.; Peters, Stephen P.; Boushey, Homer A.; Chinchilli, Vernon M.; Mauger, Dave; Tantisira, Kelan G.; Weiss, Scott T.

doi:10.1111/cea.12000

Cited by 66 publications

(44 citation statements)

References 38 publications

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“…Both C3 and C4 showed eleven genes with identical dysregulation and similar fold change magnitude (Supplemental Table E9). Supplemental Figure E2 illustrates the expression of 5 genes common to both clusters that have been previously linked to airway biology and asthma: TNFAIP3 (18–20); MIR21 (21, 22); HLA-DQA1 (23, 24); IL1RAP (25); and CCL18 (26–28). …”

Section: Resultsmentioning

confidence: 99%

Characterisation of asthma subgroups associated with circulating YKL-40 levels

et al. 2017

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The chitinase-like protein YKL-40 mediates airway inflammation, and serum levels are associated with asthma severity. However, asthma phenotypes associated with YKL-40 levels have not been precisely defined. We conducted an unsupervised cluster analysis of asthma patients treated at the Yale Center for Asthma and Airways Disease (YCAAD, n=156) to identify subgroups according to YKL-40 level. The resulting YKL-40 clusters were cross-validated in cohorts from the Severe Asthma Research Program (SARP) (n=167) and the New York University Bellevue Asthma Repository (NYUBAR) (n=341). A sputum transcriptome analysis revealed molecular pathways associated with YKL-40 subgroups. Four YKL-40 clusters (C1-4) were identified. C3 and C4 had high serum YKL-40 levels compared to C1 and C2. C3 was associated with earlier onset and longer duration of disease, severe airflow obstruction and near-fatal asthma exacerbations. C4 had the highest serum YKL-40 levels, adult onset, and less airflow obstruction but frequent exacerbations. An airway transcriptome analysis in C3 and C4 showed activation of non-Type 2 inflammatory pathways. Elevated serum YKL-40 levels were associated with two distinct clinical asthma phenotypes: one with irreversible airway obstruction and another with severe exacerbations. The YKL-40 clusters are potentially useful for identification of individuals with severe or exacerbation-prone asthma.

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Section: Resultsmentioning

confidence: 99%

Characterisation of asthma subgroups associated with circulating YKL-40 levels

et al. 2017

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“…Interestingly, a more pronounced effect of rs9273349 was observed in later-onset asthma than in childhood-onset asthma, although the difference was not significant. A recent GWAS replicated the association of this SNP with asthma and also reported notably stronger associations in the adult compared with the childhood population [6].…”

Section: Introductionmentioning

confidence: 76%

“…Evidence from several independent genome-wide association studies (GWAS) lend further support to the involvement of HLA-II loci in asthma, allergic sensitisation and increased total IgE level [4][5][6][7][8][9][10][11]. The GABRIEL consortium carried out the largest asthma GWAS to date, by genotyping 10 365 asthma patients and 16 110 controls recruited from 23 studies [4].…”

Section: Introductionmentioning

confidence: 97%

Human leukocyte antigen class II variants and adult-onset asthma: does occupational allergen exposure play a role?

Smit¹,

Strachan²,

Vermeulen³

et al. 2014

Eur Respir J

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Recently, a locus centred on rs9273349 in the HLA-DQ region emerged from genome-wide association studies of adult-onset asthma. We aimed to further investigate the role of human leukocyte antigen (HLA) class II in adult-onset asthma and a possible interaction with occupational exposures.We imputed classical HLA-II alleles from 7579 single-nucleotide polymorphisms in 6025 subjects (1202 with adult-onset asthma) from European cohorts: ECRHS, SAPALDIA, EGEA and B58C, and from surveys of bakers and agricultural workers. Based on an asthma-specific job-exposure matrix, 2629 subjects had ever been exposed to high molecular weight (HMW) allergens. We explored associations between 23 common HLA-II alleles and adult-onset asthma, and tested for gene-environment interaction with occupational exposure to HMW allergens. Interaction was also tested for rs9273349.Marginal associations of classical HLA-II alleles and adult-onset asthma were not statistically significant. Interaction was detected between the DPB1*03:01 allele and exposure to HMW allergens (p50.009), in particular to latex (p50.01). In the unexposed group, the DPB1*03:01 allele was associated with adult-onset asthma (OR 0.67, 95%CI 0.53-0.86). HMW allergen exposures did not modify the association of rs9273349 with adult-onset asthma.Common classical HLA-II alleles were not marginally associated with adult-onset asthma. The association of latex exposure and adult-onset asthma may be modified by DPB1*03:01. @ERSpublicationsIn an analysis involving .6000 European adults, classical HLA-II alleles were not associated with adult-onset asthma

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“…Nevertheless, based on the results presented in Fig. 8, there appears to be immune recognition of RV-A and RV-C epitopes by diverse HLA haplotypes, and therefore, HLA-restricted recognition does not appear to account for the genome-wide association study (GWAS) associations previously described (34,35). The low association between HLA class II haplotypes and epitope recognition has been previously reported for house dust mite allergens in relation to the HLA-DQ haplotype (36).…”

Section: Discussionmentioning

confidence: 97%

Immunodominant T-Cell Epitopes in the VP1 Capsid Protein of Rhinovirus Species A and C

Gaido

Stone

Chopra

et al. 2016

J Virol

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Rhinovirus (RV) species A and C are the most frequent cause of respiratory viral illness worldwide, and RV-C has been linked to more severe exacerbations of asthma in young children. Little is known about the immune responses to the different RV species, although studies comparing IgG1 antibody titers found impaired antibody responses to RV-C. Therefore, the aim of this study was to assess whether T-cell immunity to RV-C is similarly impaired. We measured T-cell proliferation to overlapping synthetic peptides covering the entire VP1 capsid protein of an RV-A and RV-C genotype for 20 healthy adult donors. Human leukocyte antigen (HLA) was typed in all the donors in order to investigate possible associations between the HLA type and RV peptide recognition. Total and specific IgG1 antibody titers to the VP1 proteins of both RV-A and RV-C were also measured to examine associations between the antibody and T-cell responses. We identified T-cell epitopes that are specific to and representative of each RV-A and RV-C species. These epitopes stimulated CD4 ؉ -specific T-cell proliferation, with similar magnitudes of response for both RV species. All the donors, independent of their HLA-DR or -DQ type, were able to recognize the immunodominant RV-A and -C regions of VP1. Furthermore, the presence or absence of specific antibody titers was not related to changes in T-cell recognition. Our results indicate a dissociation between the antibody and T-cell responses to rhinoviruses. The species-representative T-cell epitopes identified in this study are valuable tools for future studies investigating T-cell responses to the different RV species. IMPORTANCERhinoviruses (RVs) are mostly associated with the common cold and asthma exacerbations, although their contributions to most upper and lower respiratory tract diseases have increasingly been reported. Species C (RV-C) has been associated with more frequent and severe asthma exacerbations in young children and, along with RV-A, is the most clinically relevant species. Little is known about how our immune system responds to rhinoviruses, and there are limited tools to study specific adaptive immunity against each rhinovirus species. In this study, we identified immunodominant T-cell epitopes of the VP1 proteins of RV-A and RV-C, which are representative of each species. The study found that T-cell responses to RV-A and RV-C were of similar magnitudes, in contrast with previous findings showing RV-C-specific antibody responses were low. These findings will provide the basis for future studies on the immune response to rhinoviruses and can help elucidate the mechanisms of severity of rhinovirus-induced infections.

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HLA‐DQ strikes again: Genome‐wide association study further confirms HLA‐DQ in the diagnosis of asthma among adults

Abstract: Overall, our findings further replicate the HLA-DQ region in the pathogenesis of asthma. HLA-DQA1 is the fourth member of the HLA family found to be associated with asthma, in addition to the previously identified HLA-DRA, HLA-DQB1 and HLA-DQA2.

Cited by 66 publications

References 38 publications

Characterisation of asthma subgroups associated with circulating YKL-40 levels

Characterisation of asthma subgroups associated with circulating YKL-40 levels

Human leukocyte antigen class II variants and adult-onset asthma: does occupational allergen exposure play a role?

Immunodominant T-Cell Epitopes in the VP1 Capsid Protein of Rhinovirus Species A and C

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