Genome-wide association study identifies the SERPINB gene cluster as a susceptibility locus for food allergy

Nature Communications - Tập 8 Số 1
Ingo Marenholz1, Sarah Grosche1, Birgit Kalb1, Franz Rüschendorf1, Katharina Blümchen2, Rupert Schlags3, Neda Harandi3, Mareike Price4, Gesine Hansen4, Jürgen Seidenberg5, Holger Röblitz6, Songül Yürek7, Sebastian Tschirner7, Xiumei Hong8, Xiaobin Wang8, Georg Homuth9, Carsten Oliver Schmidt10, Markus M. Nöthen11, Norbert Hübner1, B. Niggemann7, Kirsten Beyer7, Young‐Ae Lee12
1Max-Delbrück-Center (MDC) for Molecular Medicine, 13125, Berlin, Germany
2Department of Allergy, Pulmonology and Cystic Fibrosis, Children’s Hospital, Goethe University, 60590, Frankfurt am Main, Germany
3Department of Pediatric Pneumology and Allergology, Wangen Hospital, 88239, Wangen, Germany
4Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany
5Department of Pediatric Pneumology and Allergology, Neonatology and Intensive Care, Medical Campus of University Oldenburg, 26133, Oldenburg, Germany
6Department of Pediatrics and Adolescent Medicine, Sana Klinikum Lichtenberg, 10365, Berlin, Germany
7Department of Pediatric Pneumology and Immunology, Charité University Medical Center, 13353, Berlin, Germany
8Department of Population, Family and Reproductive Health, Center on the Early Life Origins of Disease, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, 21205, USA
9Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, 17487, Greifswald, Germany
10Institute for Community Medicine, Study of Health in Pomerania/KEF, University Medicine Greifswald, 17475, Greifswald, Germany
11Institute of Human Genetics and Department of Genomics, Life & Brain Center, University of Bonn, 53127, Bonn, Germany
12Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité University Medical Center, 13125, Berlin, Germany

Tóm tắt

Abstract

Genetic factors and mechanisms underlying food allergy are largely unknown. Due to heterogeneity of symptoms a reliable diagnosis is often difficult to make. Here, we report a genome-wide association study on food allergy diagnosed by oral food challenge in 497 cases and 2387 controls. We identify five loci at genome-wide significance, the clade B serpin (SERPINB) gene cluster at 18q21.3, the cytokine gene cluster at 5q31.1, the filaggrin gene, theC11orf30/LRRC32locus, and the human leukocyte antigen (HLA) region. Stratifying the results for the causative food demonstrates that association of the HLA locus is peanut allergy-specific whereas the other four loci increase the risk for any food allergy. Variants in the SERPINB gene cluster are associated withSERPINB10expression in leukocytes. Moreover, SERPINB genes are highly expressed in the esophagus. All identified loci are involved in immunological regulation or epithelial barrier function, emphasizing the role of both mechanisms in food allergy.

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Tài liệu tham khảo

Osborne, N. J. et al. Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants. J. Allergy Clin. Immunol. 127, 668–676.e1-2 (2011).

Tang, M. L. & Mullins, R. J. Food allergy: is prevalence increasing? Intern. Med. J. 47, 256–261 (2017).

Muraro, A. et al. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy 69, 1008–1025 (2014).

Nwaru, B. I. et al. Prevalence of common food allergies in Europe: a systematic review and meta-analysis. Allergy 69, 992–1007 (2014).

Grabenhenrich, L. B. et al. Anaphylaxis in children and adolescents: The European Anaphylaxis Registry. J. Allergy Clin. Immunol. 137, 1128–1137.e1 (2016).

Panesar, S. S. et al. The epidemiology of anaphylaxis in Europe: a systematic review. Allergy 68, 1353–1361 (2013).

Braganza, S. C., Acworth, J. P., McKinnon, D. R., Peake, J. E. & Brown, A. F. Paediatric emergency department anaphylaxis: different patterns from adults. Arch. Dis. Child. 91, 159–163 (2006).

Sicherer, S. H. et al. Genetics of peanut allergy: a twin study. J. Allergy Clin. Immunol. 106, 53–56 (2000).

Ullemar, V. et al. Heritability and confirmation of genetic association studies for childhood asthma in twins. Allergy 71, 230–238 (2016).

Brown, S. J. et al. Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J. Allergy Clin. Immunol. 127, 661–667 (2011).

Howell, W. M., Turner, S. J., Hourihane, J. O., Dean, T. P. & Warner, J. O. HLA class II DRB1, DQB1 and DPB1 genotypic associations with peanut allergy: evidence from a family-based and case-control study. Clin. Exp. Allergy 28, 156–162 (1998).

Hand, S. et al. Human leucocyte antigen polymorphisms in nut-allergic patients in South Wales. Clin. Exp. Allergy 34, 720–724 (2004).

Madore, A. M. et al. HLA-DQB1*02 and DQB1*06:03P are associated with peanut allergy. Eur. J. Hum. Genet. 21, 1181–1184 (2013).

Hong, X. et al. Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children. Nat. Commun. 6, 6304 (2015).

Sampson, H. A. et al. Standardizing double-blind, placebo-controlled oral food challenges: American academy of allergy, asthma & immunology-European academy of allergy and clinical immunology PRACTALL consensus report. J. Allergy Clin. Immunol. 130, 1260–1274 (2012).

Schmermund, A. et al. Assessment of clinically silent atherosclerotic disease and established and novel risk factors for predicting myocardial infarction and cardiac death in healthy middle-aged subjects: rationale and design of the Heinz Nixdorf RECALL Study. Risk Factors, evaluation of coronary calcium and lifestyle. Am. Heart J. 144, 212–218 (2002).

McCarthy, S. et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279–1283 (2016).

Volzke, H. et al. Cohort profile: the study of health in Pomerania. Int. J. Epidemiol. 40, 294–307 (2011).

Palmer, C. N. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat. Genet. 38, 441–446 (2006).

Paternoster, L. et al. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. Nat. Genet. 47, 1449–1456 (2015).

Machiela, M. J. & Chanock, S. J. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics 31, 3555–3557 (2015).

McLaren, W. et al. The Ensembl variant effect predictor. Genome Biol. 17, 122 (2016).

Goi, C., Little, P., & Xie, C. Cell-type and transcription factor specific enrichment of transcriptional cofactor motifs in ENCODE ChIP-seq data. BMC Genom. 14, S2 (2013).

Ward, L. D. & Kellis, M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucl. Acids Res. 40, D930–D934 (2012).

Martino, D. J. et al. Genomewide association study of peanut allergy reproduces association with amino acid polymorphisms in HLA-DRB1. Clin. Exp. Allergy 47, 217–223 (2017).

Marenholz, I. et al. Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J. Allergy Clin. Immunol. 118, 866–871 (2006).

van den Oord, R. A. & Sheikh, A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. BMJ 339, b2433 (2009).

Venkataraman, D. et al. Filaggrin loss-of-function mutations are associated with food allergy in childhood and adolescence. J. Allergy Clin. Immunol. 134, 876–882.e4 (2014).

Smith, S. A. & Dale, B. A. Immunologic localization of filaggrin in human oral epithelia and correlation with keratinization. J. Invest. Dermatol. 86, 168–172 (1986).

Simon, D., Radonjic-Hosli, S., Straumann, A., Yousefi, S. & Simon, H. U. Active eosinophilic esophagitis is characterized by epithelial barrier defects and eosinophil extracellular trap formation. Allergy 70, 443–452 (2015).

Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

Nair, R. P. et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat. Genet. 41, 199–204 (2009).

Paternoster, L., et al. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. Nat. Genet. 44, 187–192 (2011).

Vladich, F. D. et al. IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation. J. Clin. Invest. 115, 747–754 (2005).

Noval Rivas, M. et al. Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity 42, 512–523 (2015).

Esparza-Gordillo, J. et al. A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat. Genet. 41, 596–601 (2009).

Marenholz, I. et al. The eczema risk variant on chromosome 11q13 (rs7927894) in the population-based ALSPAC cohort: a novel susceptibility factor for asthma and hay fever. Hum. Mol. Genet. 20, 2443–2449 (2011).

Ferreira, M. A. et al. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 378, 1006–1014 (2011).

Welter, D. et al. The NHGRI GWAS catalog, a curated resource of SNP-trait associations. Nucl. Acids Res. 42, D1001–D1006 (2014).

Marenholz, I. et al. Meta-analysis identifies seven susceptibility loci involved in the atopic march. Nat. Commun. 6, 8804 (2015).

Kubo, A. et al. Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis. Am. J. Hum. Genet. 93, 945–956 (2013).

Bruhn, S. et al. Combining gene expression microarray- and cluster analysis with sequence-based predictions to identify regulators of IL-13 in allergy. Cytokine 60, 736–740 (2012).

Davydov, I. V., Krammer, P. H. & Li-Weber, M. Nuclear factor-IL6 activates the human IL-4 promoter in T cells. J. Immunol. 155, 5273–5279 (1995).

Zhang, J. et al. Evidence for multiple promoters of the human IL-5 receptor alpha subunit gene: a novel 6-base pair element determines cell-specific promoter function. J. Immunol. 159, 5412–5421 (1997).

Simpson-Abelson, M. R. et al. C/EBPbeta promotes immunity to oral Candidiasis through regulation of beta-defensins. PLoS ONE 10, e0136538 (2015).

Stritesky, G. L. et al. The transcription factor STAT3 is required for T helper 2 cell development. Immunity 34, 39–49 (2011).

Ray, R. et al. Uteroglobin suppresses SCCA gene expression associated with allergic asthma. J. Biol. Chem. 280, 9761–9764 (2005).

Mitsuishi, K. et al. The squamous cell carcinoma antigens as relevant biomarkers of atopic dermatitis. Clin. Exp. Allergy 35, 1327–1333 (2005).

Yuyama, N. et al. Analysis of novel disease-related genes in bronchial asthma. Cytokine 19, 287–296 (2002).

Sivaprasad, U. et al. SERPINB3/B4 contributes to early inflammation and barrier dysfunction in an experimental murine model of atopic dermatitis. J. Invest. Dermatol. 135, 160–169 (2015).

Schroder, W. A. et al. SerpinB2 deficiency results in a stratum corneum defect and increased sensitivity to topically applied inflammatory agents. Am. J. Pathol. 186, 1511–1523 (2016).

Woodruff, P. G. et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc. Natl Acad. Sci. USA 104, 15858–15863 (2007).

Lilly, C. M., Tateno, H., Oguma, T., Israel, E. & Sonna, L. A. Effects of allergen challenge on airway epithelial cell gene expression. Am. J. Respir. Crit. Care Med. 171, 579–586 (2005).

Zhao, A. et al. SerpinB2 is critical to Th2 immunity against enteric nematode infection. J. Immunol. 190, 5779–5787 (2013).

Visscher, P. M., Brown, M. A., McCarthy, M. I. & Yang, J. Five years of GWAS discovery. Am. J. Hum. Genet. 90, 7–24 (2012).

Tenesa, A. & Haley, C. S. The heritability of human disease: estimation, uses and abuses. Nat. Rev. Genet. 14, 139–149 (2013).

Purcell, S., Cherny, S. S. & Sham, P. C. Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19, 149–150 (2003).

Hanifin, J. M. & Rajka, G. Diagnostic features of atopic dermatitis. Acta Derm. 92, 44–47 (1980).

Williams, H. C., Burney, P. G., Strachan, D. & Hay, R. J. The U.K. Working Party’s Diagnostic Criteria for Atopic Dermatitis. II. Observer variation of clinical diagnosis and signs of atopic dermatitis. Br. J. Dermatol. 131, 397–405 (1994).

Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

Das, S. et al. Next-generation genotype imputation service and methods. Nat. Genet. 48, 1284–1287 (2016).

Johnson, E. O. et al. Imputation across genotyping arrays for genome-wide association studies: assessment of bias and a correction strategy. Hum. Genet. 132, 509–522 (2013).

Delaneau, O., Zagury, J. F. & Marchini, J. Improved whole-chromosome phasing for disease and population genetic studies. Nat. Methods 10, 5–6 (2013).

Lippert, C. et al. FaST linear mixed models for genome-wide association studies. Nat. Methods 8, 833–835 (2011).

Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

GTEx Consortium. Human genomics. The Genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).

Arnold, M., Raffler, J., Pfeufer, A., Suhre, K. & Kastenmuller, G. SNiPA: an interactive, genetic variant-centered annotation browser. Bioinformatics 31, 1334–1336 (2015).

Ellinghaus, D. et al. High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat. Genet. 45, 808–812 (2013).

Bulik-Sullivan, B. K. et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).

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