Mechanisms of allergy/immunology
Shared genetic variants suggest common pathways in allergy and autoimmune diseases

https://doi.org/10.1016/j.jaci.2016.10.055Get rights and content

Background

The relationship between allergy and autoimmune disorders is complex and poorly understood.

Objective

We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms.

Methods

We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases.

Results

Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases.

Conclusion

We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.

Section snippets

Study group

To obtain the largest possible GWAS data set for allergy, we meta-analyzed results from 2 recent GWASs on self-reported allergy9 and sensitization,10 including approximately 2.2 million directly genotyped and imputed single nucleotide polymorphisms (SNPs), by using a fixed-effects model. The self-reported allergy data set comprised 23,335 patients with self-reported allergy for cat, dust mite, and/or pollen allergy and 26,311 control subjects without symptoms. The allergic sensitization data

Allergy meta-analysis

Using the joint meta-analysis on combined data from allergic sensitization and self-reported allergy, we increased the number of allergy-associated SNPs compared with the previous GWAS (see Fig E2 in this article's Online Repository at www.jacionline.org), resulting in a total number of 19 genome-wide significant loci (see Fig E3 in this article's Online Repository at www.jacionline.org). One of these, rs11122898 near ANAPC1/MERKT (P = 1.9e-8), has not previously been associated with allergy or

Discussion

Our study demonstrated substantial commonalities between allergy and autoimmune diseases in terms of susceptibility loci, genetic pathways, and genomic regulatory sites (DHS). This overlap in genetic mechanisms seemed to be a general phenomenon for allergy and autoimmune diseases and distinct from other diseases. Our study identifies a substantial number of novel overlapping loci for allergy and autoimmune diseases suggesting both shared (increasing risk of both autoimmune and allergic

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    Disclosure of potential conflict of interest: E. Kreiner is employed at Novo Nordisk A/S. A. Simpson has received a grant from the Medical Research Council. J. Y. Tung is employed by and receives stock/stock options from 23andMe. G. H. Koppelman has received grants from the Netherlands Lung Foundation, Stichting Astma Bestrijding, Ubbo Emmius Foundation, and TEVA, The Netherlands. D. S. Postma has consultant arrangements with Astra Zeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Takeda, and TEVA and has received grants from AstraZeneca, Chiesi, Genentech, GlaxoSmithKline, and Roche. C. E. Pennell has received grants from the National Health Medical Research Council, Telethon, and Telethon-Perth Children's Hospital Research Fund; is employed by the University of Western Australia; and has received travel support for invited presentations from Raine Study Core Funds, Haematology Association of Australia, Global Obstetric Update, March of Dimes and Burrows Wellcome. A. Custovic has received personal fees from Novartis, Regeneron/Sanofi, ALK-Abelló, Bayer, and Thermo Fisher. M. A. Ferreira has received a grant from the National Health Medical Research Council of Australia (Project Grant 613627). J. Henderson has received grants from the Medical Research Council, Wellcome, and 23andMe. D. Hinds has received a grant from the National Heart, Lung, and Blood Institute (grant 1R43HL115873-01) and is employed by and has received stock/stock options from 23andMe. H. Bisgaard has received grants from the Danish Ministry of Health, the Lundbeck Foundation, and the Danish Strategic Research Foundation and has consultant arrangements with Chiesi Pharmaceuticals and Boehringer Ingelheim. K. Bønnelykke has received grants from the Danish Ministry of Health, the Lundbeck Foundation, and the Danish Strategic Research Foundation. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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