Laulajainen‑Hongisto et al. Clin Transl Allergy (2020) 10:45 https://doi.org/10.1186/s13601‑020‑00347‑6 Clinical and Translational Allergy REVIEW Open Access Genomics of asthma, allergy and chronic rhinosinusitis: novel concepts and relevance in airway mucosa Anu Laulajainen‑Hongisto1,2†, Annina Lyly1,3*† , Tanzeela Hanif4, Kishor Dhaygude4, Matti Kankainen5,6,7, Risto Renkonen4,5, Kati Donner6, Pirkko Mattila4,6, Tuomas Jartti8, Jean Bousquet9,10,11, Paula Kauppi3† and Sanna Toppila‑Salmi3,4† Abstract Genome wide association studies (GWASs) have revealed several airway disease‑associated risk loci. Their role in the onset of asthma, allergic rhinitis (AR) or chronic rhinosinusitis (CRS), however, is not yet fully understood. The aim of this review is to evaluate the airway relevance of loci and genes identifed in GWAS studies. GWASs were searched from databases, and a list of loci associating signifcantly (p < 10–8) with asthma, AR and CRS was created. This yielded a total of 267 signifcantly asthma/AR–associated loci from 31 GWASs. No signifcant CRS ‑associated loci were found in this search. A total of 170 protein coding genes were connected to these loci. Of these, 76/170 (44%) showed bronchial epithelial protein expression in stained microscopic fgures of Human Protein Atlas (HPA), and 61/170 (36%) had a literature report of having airway epithelial function. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation analyses were performed, and 19 functional protein categories were found as signif‑ cantly (p < 0.05) enriched among these genes. These were related to cytokine production, cell activation and adaptive immune response, and all were strongly connected in network analysis. We also identifed 15 protein pathways that were signifcantly (p < 0.05) enriched in these genes, related to T‑helper cell diferentiation, virus infection, JAK‑STAT signaling pathway, and asthma. A third of GWAS‑level risk loci genes of asthma or AR seemed to have airway epithe‑ lial functions according to our database and literature searches. In addition, many of the risk loci genes were immu‑ nity related. Some risk loci genes also related to metabolism, neuro‑musculoskeletal or other functions. Functions overlapped and formed a strong network in our pathway analyses and are worth future studies of biomarker and therapeutics. Keywords: Asthma, Allergic rhinitis, Airway epithelium, GWAS, Gene ontology, Pathway Background caused by allergen binding to specifc IgE in the nasal Asthma, allergic rhinitis (AR) and chronic rhinosinusi- mucosa of a sensitized individual, leading to infamma- tis (CRS) are multifactorial chronic airway diseases that tion and symptoms of allergy. Te prevalence of AR has share some common pathogenetic mechanisms. AR is increased in the Western countries over the last few dec- ades and it nowadays has been estimated to afect up to *Correspondence: [email protected] 10–25% of the population [1]. Asthma is a chronic pul- †Anu Laulajainen‑Hongisto and Annina Lyly shared frst authorship monary disease with airway infammation, bronchial †Paula Kauppi and Sanna Toppila‑Salmi shared last authorship hyperresponsiveness and recurrent, reversible airfow 1 Department of Otorhinolaryngology–Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Kasarmikatu 11‑13, obstruction. Exacerbations are common both in asthma P.O.Box 263, 00029 HUS Helsinki, Finland and in CRS, which is a chronic symptomatic infamma- Full list of author information is available at the end of the article tion of the sinonasal tract. Asthma and CRS both afect © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Laulajainen‑Hongisto et al. Clin Transl Allergy (2020) 10:45 Page 2 of 17 about 3–10% of the Western population [2–4]. Risk fac- previously undescribed and unexpected genetic compo- tors for asthma, AR and CRS include genetic predisposi- nents, highlighting the method’s freedom of preconcep- tion, other allergic diseases, infections and environmental tions [23]. factors including exposure to tobacco smoke and air pol- Risk factors and pathogenetic mechanisms of aller- lution [5–7]. gic diseases are also interrelated and share partly same Many of the environmental risk factors in the patho- mechanisms, which is why we took this broad approach. genesis of asthma and CRS are linked to disrupted inter- Our aim was to review GWASs identifed asthma, AR play between epithelial barriers, particles, allergens and and CRS related genes, and to evaluate their relevance microbes [8, 9]. Type 2 biased infammation with recruit- in airway mucosal functions. Tis review is based on an ment of eosinophils, basophils, and T-cells, and release extensive literature search, and several database searches of cytokines is common in atopic asthma and AR [10, (Fig. 1). 11]. Epithelial cells are in contact with microbes, which increasingly have been shown to have a role in infamma- GWAS catalog‑search tory diseases [12, 13]. Recent studies have also found that Te GWAS catalog containing 11,598 unique SNPs, altered airway microbiome composition might be associ- was downloaded from the National Human Genome ated with asthma [14], seasonal AR [15–17], or children Research Institute (NHGRI) website (https ://www.ebi. with rhinitis [18]. ac.uk/gwas/) on January 18, 2018. We created a list of 267 Genetic inheritance has been estimated to explain SNPs associating signifcantly (p < 10 exp -8) with asthma 25–80% of asthma risk [19] and up to 90% of AR risk [20]. and/or AR provided in the Additional fle 1: Table S1. Te genetic predisposition of CRS seems to vary accord- Tere were no SNPs associating signifcantly with CRS. ing to CRS type. Although an increased risk is associated Gene symbols were mapped onto chromosomes by using with both types, the familial risk of CRS with nasal pol- Ensemble Karyotype viewer (https ://www.ensem bl.org/ yps (CRSwNP) has been found signifcantly higher than Homo_sapie ns/Locat ion/Genom e) (Additional fle 1: that of CRS without nasal polyps (CRSsNP) in a popula- Table S1). Of these 267 SNPs, we selected the SNPs which tion based study conducted in Utah [21]. were assigned to a protein coding gene or those reported Large collaborative twin studies and GWAS pro- to have a protein coding gene as the nearest gene [24]. jects have helped establishing genetic components for Using this strategy, we identifed a total of 170 protein asthma, CRS and AR. Kim et al. [22] summarized the coding genes (Additional fle 1: Table S2). Of them, 21 results of 42 GWASs of asthmatic subjects and controls genes were connected to several SNPs and/or identifed and asthma-related traits. Te most replicated loci with in diferent studies. A Manhattan plot (https ://biore nder. –8 genome-wide signifcant (p < 5 × 10 ) were the cluster com/) of SNPs was generated (Fig. 2), showing that sus- of genes at the 17q12–21, including ORMDL3 (oroso- ceptibility genes were distributed to all chromosomes mucoid-like 3), GSDMB (gasdermin B), and GSDMA (except sex chromosomes). Several genes were found to (gasdermin A), specifc to childhood-onset disease. Te locate in chromosomes 1, 5, 6, or 17. next three loci achieving signifcant p-values included loci 2q12 in the vicinity of several interleukin receptor Database and literature search of airway genes, namely IL1RL1, IL1RL2, and IL18R1, a region expression of the protein expressing genes on 5q22 that contains the mitochondrial solute carrier Information about the 170 protein coding genes in Gene gene SLC25A46 and the hemopoietic cytokine gene Cards, NCBI Gene Expression Omnibus (GEOacces- TSLP and a complex region located within the major sion: GSE5057 and GSE40364), and Human Protein Atlas histocompatibility locus 6p21. While these multigene (HPA) (https ://www.prote inatl as.org/) was examined loci are challenging to dissect, it is notable that IL1RL1 (Fig. 3). We also collected lung, bronchial, and naso- encodes the receptor for IL-33. Te gene that encodes pharyngeal expressions of these genes from the Genotype IL-33 is separately implicated in the genetic etiology of tissue expression portal (GTEx), expressed as Reads Per asthma through the ffth most replicated locus on chro- Kilobase Million (RPKM) (Additional fle 1: Table S2). mosome 9p24. Nasopharyngeal/bronchial protein expression informa- Like many other complex diseases, the development of tion was obtained from immunohistochemically stained asthma or AR requires genetic predisposition and appro- photomicrographs of HPA, and the staining intensity priate timing of environmental exposures. GWASs have was semiquantitatively scored as 0–3 (0 = no, 1 = mild, been able to identify and replicate several signifcant 2 = moderate, 3 = strong staining). A total of 76/170 risk regions in large sample sets [10]. Among already (44%) of these genes showed bronchial epithelial protein known important asthma loci, GWASs have also revealed expression and 69/170 (41%) showed nasopharyngeal epi- thelial protein expression in stained microscopic fgures Laulajainen‑Hongisto et al.
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