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J Allergy Clin Immunol. 2019 Feb;143(2):691-699. doi: 10.1016/j.jaci.2018.03.012. Epub 2018 Apr 19.

Eleven loci with new reproducible genetic associations with allergic disease risk.

Author information

1
Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia. Electronic address: manuel.ferreira@qimrberghofer.edu.au.
2
Epidemiology, University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.
3
Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
4
Max Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany; Clinic for Pediatric Allergy, Experimental and Clinical Research Center of Charité Universitätsmedizin Berlin and Max Delbrück Center, Berlin, Germany.
5
23andMe, Inc, Mountain View, Calif.
6
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, Calif.
7
Department Biological Psychology, Netherlands Twin Register, Vrije University, Amsterdam, The Netherlands.
8
Department of Medical Epidemiology and Biostatistics and the Swedish Twin Registry, Karolinska Institutet, Stockholm, Sweden.
9
Max Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany.
10
Division of Research, Kaiser Permanente Northern California, Oakland, Calif.
11
Department of Medical Epidemiology and Biostatistics and the Swedish Twin Registry, Karolinska Institutet, Stockholm, Sweden; Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
12
University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Pediatric Pulmonology and Pediatric Allergology, and University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.
13
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.

Abstract

BACKGROUND:

A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities.

OBJECTIVE:

We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects.

METHODS:

We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study.

RESULTS:

Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10-6. Of these, 20 were also significantly associated (P < .05/30 = .0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress TH2 responses.

CONCLUSION:

Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.

KEYWORDS:

Rhinitis; atopic dermatitis; atopy; genome-wide association study; transcriptome

PMID:
29679657
DOI:
10.1016/j.jaci.2018.03.012

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