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- W2783222712 abstract "Previously, we identified the HLA region as a risk factor for peanut allergy (PA); this observation is supported further by 2 independent genome-wide association studies (GWASs).1Hong X. Hao K. Ladd-Acosta C. Hansen K.D. Tsai H.J. Liu X. et al.Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children.Nat Commun. 2015; 6: 6304Crossref PubMed Scopus (163) Google Scholar, 2Martino D.J. Ashley S. Koplin J. Ellis J. Saffery R. Dharmage S.C. et al.Genomewide association study of peanut allergy reproduces association with amino acid polymorphisms in HLA-DRB1.Clin Exp Allergy. 2017; 47: 217-223Crossref PubMed Scopus (34) Google Scholar The HLA class II genes (including HLA-DR, HLA-DQ, and HLA-DP) encode molecules involved in presentation of extracellular antigens, such as peanut allergens, to T lymphocytes, which in turn mediates B-cell antibody production. We used the Canadian Peanut Allergy Registry (CanPAR) and the Busselton Health Study3James A.L. Knuiman M.W. Divitini M.L. Hui J. Hunter M. Palmer L.J. et al.Changes in the prevalence of asthma in adults since 1966: the Busselton health study.Eur Respir J. 2010; 35: 273-278Crossref PubMed Scopus (66) Google Scholar to conduct the largest GWAS for PA to date. Here we report analysis of the HLA region and a meta-analysis with data from 6 additional studies, which confirms and narrows the region of interest to HLA-DQB1 and establishes independence from asthma loci. In the CanPAR GWAS more than 7.8 million single nucleotide polymorphisms (SNPs; 1,388,588 genotyped and 6,441,607 imputed) and 1776 subjects (850 cases and 926 control subjects) passed quality control. Detailed methods, including PA inclusion criteria (see Table E1 in this article's Online Repository at www.jacionline.org), quality control, and imputation, were published previously (see Figs E1 and E2 in this article's Online Repository at www.jacionline.org).4Asai Y. Eslami A. van Ginkel C.D. Akhabir L. Wan M. Ellis G. et al.Genome-wide association study and meta-analysis in multiple populations identifies new loci for peanut allergy and establishes c11orf30/EMSY as a genetic risk factor for food allergy.J Allergy Clin Immunol. 2017; ([Epub ahead of print])Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar In addition to the CanPAR GWAS, 6 additional studies were included in a meta-analysis of the HLA region: 2 American studies (the Chicago Food Allergy study [n = 2,197; 316 PA cases])1Hong X. Hao K. Ladd-Acosta C. Hansen K.D. Tsai H.J. Liu X. et al.Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children.Nat Commun. 2015; 6: 6304Crossref PubMed Scopus (163) Google Scholar and the Genetic Epidemiology Research on Aging (GERA) cohort (n = 29,053; 5108 self-reported food allergy]),5Hoffmann T.J. Kvale M.N. Hesselson S.E. Zhan Y. Aquino C. Cao Y. et al.Next generation genome-wide association tool: design and coverage of a high-throughput European-optimized SNP array.Genomics. 2011; 98: 79-89Crossref PubMed Scopus (141) Google Scholar the Australian HealthNuts study (n = 221; 73 PA cases),2Martino D.J. Ashley S. Koplin J. Ellis J. Saffery R. Dharmage S.C. et al.Genomewide association study of peanut allergy reproduces association with amino acid polymorphisms in HLA-DRB1.Clin Exp Allergy. 2017; 47: 217-223Crossref PubMed Scopus (34) Google Scholar and the German Understanding Food Allergy study (n = 2,592; 205 PA cases).2Martino D.J. Ashley S. Koplin J. Ellis J. Saffery R. Dharmage S.C. et al.Genomewide association study of peanut allergy reproduces association with amino acid polymorphisms in HLA-DRB1.Clin Exp Allergy. 2017; 47: 217-223Crossref PubMed Scopus (34) Google Scholar Genotyping for HLA SNPs was conducted in Dutch subjects from 2 studies: IDEAL and GENEVA (n = 1,512; 138 PA cases). Both the IDEAL and GENEVA studies include cases of general food allergy.6van Ginkel C.D. Flokstra-de Blok B.M. Kollen B.J. Kukler J. Koppelman G.H. Dubois A.E. Loss-of-function variants of the filaggrin gene are associated with clinical reactivity to foods.Allergy. 2015; 70: 461-464Crossref PubMed Scopus (25) Google Scholar See Table E2 in this article's Online Repository at www.jacionline.org for study and phenotype descriptions.4Asai Y. Eslami A. van Ginkel C.D. Akhabir L. Wan M. Ellis G. et al.Genome-wide association study and meta-analysis in multiple populations identifies new loci for peanut allergy and establishes c11orf30/EMSY as a genetic risk factor for food allergy.J Allergy Clin Immunol. 2017; ([Epub ahead of print])Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Fixed- and random-effects models evaluate heterogeneity and require point estimates. Because the Chicago Food Allergy and Understanding Food Allergy studies provided P value and sample sizes only, for meta-analyses, P values were obtained by using the Stouffer weighted z score. We conducted stratified analyses on genotyped SNPs to evaluate associations with reaction severity (mild, moderate, or severe; see Tables E3 and E4 in this article's Online Repository at www.jacionline.org), specificity to PA, and asthma comorbidity. Asthma history in conjunction with PA reaction severity was also examined because these features are known to be correlated. Patients with PA self-identified as ever having asthma, and patients with PA with no asthma were analyzed separately against control subjects for 6 asthma SNPs identified from the GWAS catalog (see https://www.ebi.ac.uk/gwas/). Eighty-five SNPs located in HLA on chromosome 6, in the region of HLA-DQB1, reached genome-wide significance (Fig 1 and see Fig E3 in this article's Online Repository at www.jacionline.org) in the CanPAR GWAS. The most significant SNP was rs1049213, which is located in the 3′ untranslated region of HLA-DQB1 (P = 1.82 × 10−11, see Table E5 in this article's Online Repository at www.jacionline.org). Meta-analysis identified rs1063347 (P = 3.67 × 10−23, see Table E5) and narrowed the region of interest to HLA-DQB1. The significance of the top imputed (rs1049213) and genotyped (rs3134976) SNPs increased to a P value of 10−21 in the meta-analysis (see Table E5). The stratified analysis demonstrated a trend for increased odds ratios (ORs) with increasing reaction severity (see Table E6 in this article's Online Repository at www.jacionline.org) and with PA alone versus PA and other food allergy (see Table E7 in this article's Online Repository at www.jacionline.org). Those with a mild reaction history without other food allergy had a statistically significant increase in ORs for SNPs in HLA (rs17612852, rs9275596, and rs1612904), despite a small number of cases; this was not observed in patients with moderate or severe PA. To evaluate the independence of PA GWAS associations from asthma comorbidity, Canadian patients with PA were stratified by the presence or absence of self-reported asthma and changes in effect sizes, and P values were evaluated. There was a higher proportion of asthmatic patients in the severe PA group compared with all cases (76% vs 64%, P = .003). There was no difference in ORs for HLA SNPs in asthmatic and nonasthmatic patients with PA (Table I). This is of interest because asthma comorbidity increases PA severity and the presence of PA increases asthma morbidity and mortality.Table IStratified analysis with and without asthma for the top HLA CanPAR GWAS locirs no.PositionORAll patients (850 cases, 926 control subjects)Patients without asthma (305 cases, 926 control subjects)Patients with asthma (545 cases, 926 control subjects)Lower 95% CIUpper 95% CIP valueORLower 95% CIUpper 95% CIP valueP value∗P value when the OR of the subgroup was compared with the OR of all cases and control subjects.ORLower 95% CIUpper 95% CIP valueP value∗P value when the OR of the subgroup was compared with the OR of all cases and control subjects.rs3134976326523052.111.682.662.15 × 10−102.201.632.972.75 × 10−7.832.031.582.603.39 × 10−8.81rs3134994326376802.111.682.662.15 × 10−102.201.632.972.75 × 10−7.832.031.582.603.39 × 10−8.81rs3135006326671192.101.672.642.45 × 10−102.191.632.962.75 × 10−7.822.021.572.593.59 × 10−8.82rs3134995326720892.101.672.653.17 × 10−102.181.612.943.98 × 10−7.852.011.572.594.50 × 10−8.81rs3135190326679462.081.652.624.66 × 10−102.161.602.924.66 × 10−7.842.001.552.565.96 × 10−8.81rs1049053326344052.081.652.614.66 × 10−102.191.622.962.75 × 10−7.781.981.542.547.87 × 10−8.79rs1049225326277472.081.652.614.66 × 10−102.191.622.962.75 × 10−7.781.981.542.547.87 × 10−8.79rs17612852326205721.991.592.491.86 × 10−92.101.572.815.44 × 10−7.771.911.502.452.34 × 10−7.82rs9275596326816311.761.432.181.04 × 10−71.811.382.381.63 × 10−5.881.681.342.118.59 × 10−6.76rs1612904326690181.761.422.161.36 × 10−71.801.372.362.14 × 10−5.881.671.332.101.03 × 10−5.75rs3135002326684391.971.532.541.61 × 10−71.881.352.631.91 × 10−4.831.991.512.631.17 × 10−6.96rs7774434326575780.580.470.712.22 × 10−70.610.460.815.82 × 10−4.770.570.450.711.51 × 10−6.87rs1049056326343690.470.360.632.75 × 10−70.480.320.723.71 × 10−4.940.480.340.661.19 × 10−5.96rs4947344326778461.711.392.114.19 × 10−71.881.442.463.48 × 10−6.581.561.241.961.23 × 10−4.55rs1794275326712480.510.390.678.22 × 10−70.570.400.801.47 × 10−3.650.480.350.653.01 × 10−6.77rs7767167327651821.951.492.551.12 × 10−61.761.212.552.79 × 10−3.672.101.582.804.19 × 10−7.70∗ P value when the OR of the subgroup was compared with the OR of all cases and control subjects. Open table in a new tab Examination of the HLA region associated with PA in the GWAS catalog (http://www.ebi.ac.uk/gwas/) identified 8 asthma SNPs in the same region as the PA locus; of these, 6 were genotyped in CanPAR and are interspersed in the same region as our meta-analysis (see Fig E3). We found no difference in ORs between asthmatic and nonasthmatic patients with PA and no genome-wide significant associations with PA in the CanPAR sample (see Table E8 in this article's Online Repository at www.jacionline.org). The Genotype-Tissue Expression (gtexportal.org)7GTEx ConsortiumThe Genotype-Tissue Expression (GTEx) project.Nat Genet. 2013; 45: 580-585Crossref PubMed Scopus (4307) Google Scholar and Gene Expression Omnibus (ncbi.nlm.nih.gov/geo)8Edgar R. Domrachev M. Lash A.E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository.Nucleic Acids Res. 2002; 30: 207-210Crossref PubMed Scopus (8465) Google Scholar databases were interrogated for expression quantitative trait loci (eQTLs) in the HLA region. Results were then narrowed to the esophageal mucosa (P ≤ 1.0 × 10−6), which identified a number of genes regulated by SNPs in this region (see Fig E3). In this study we have confirmed HLA as a PA susceptibility locus. The relationship of PA to HLA-DQB1 is likely independent of asthma because association results stratified by asthma (Table I) demonstrate no significant changes and no asthma GWAS SNPs are significant in CanPAR (see Table E8). Although confounding by asthma might never be controlled fully, the independence of PA associations from asthma suggests a lack of pleiotropy at this locus (see Fig E3). The presence of genetic risk factors for multiple atopic conditions within HLA, all at genome-wide significance, and our results demonstrating that HLA-DQB1 SNPs identified in CanPAR are independent of asthma and numerous eQTLs identified in the region suggest that this region is associated with the cause of several allergic phenotypes. The HLA class II region has been associated with various allergic diseases. However, these earlier studies and the data presented here suggest that the HLA variants underlying these phenotypes are specific to each trait. This might reflect differences in the efficiency of antigen presentation as a result of the alternate alleles at each locus. The numerous eQTLs identified in the region suggest a potential underlying mechanism for association with PA. Further discussion is provided in the Methods and Discussion sections in this article's Online Repository at www.jacionline.org. We conclude that variants in HLA-DQB1 are associated with PA, but the relationship to general food allergy is difficult to assess because PA was an ascertainment criterion for CanPAR. The importance of phenotyping is evident by the sizable changes in P values when a large cohort of self-reported patients with food allergy, who might have a high rate of misclassification,9Rona R.J. Keil T. Summers C. Gislason D. Zuidmeer L. Sodergren E. et al.The prevalence of food allergy: a meta-analysis.J Allergy Clin Immunol. 2007; 120: 638-646Abstract Full Text Full Text PDF PubMed Scopus (1053) Google Scholar was added to the meta-analysis. Inclusion of the GERA study increased the sample size but might not have increased the power because of self-reported phenotypes. The strengths of this GWAS include the sample size and clinical data available, allowing for subanalyses that indicate the relationship between PA and HLA is independent of asthma. Association results are further supported by evidence that this is a regulatory region, as demonstrated by the numerous eQTLs. We wish to thank the subjects and parents who participated in this study and in the CanPAR registry. We acknowledge Basia Rogula, who assisted in quality control; JinCheol Choi, who assisted with figure development; Jessica Que, who assisted with SNP annotation; Reza Alizadehfar, Edmund Chan, Whitney Steber, Chynace Van Lambalgen, Heather Waldhauser, Greg Shand, Elizabeth Turnbull, Popi Panaritis, and Peter Hull, who assisted in data/DNA collection for CanPAR; and Peter Paré for his valuable comments. Download .docx (.12 MB) Help with docx files Online Repository text Download .docx (.13 MB) Help with docx files E-Tables 1-8 Download .doc (.06 MB) Help with doc files Fig E2 Download .pdf (.09 MB) Help with pdf files Fig E3" @default.
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- W2783222712 date "2018-04-01" @default.
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- W2783222712 title "A Canadian genome-wide association study and meta-analysis confirm HLA as a risk factor for peanut allergy independent of asthma" @default.
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- W2783222712 doi "https://doi.org/10.1016/j.jaci.2017.10.047" @default.
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