A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order

doi:10.1016/j.jaci.2011.08.030

Journal of Allergy and Clinical Immunology

Volume 128, Issue 5, November 2011, Pages 996-1005

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https://doi.org/10.1016/j.jaci.2011.08.030 Get rights and content

Background

Hay fever or seasonal allergic rhinitis (AR) is a chronic disorder associated with IgE sensitization to grass. The underlying genetic variants have not been studied comprehensively. There is overwhelming evidence that those who have older siblings have less AR, although the mechanism for this remains unclear.

Objective

We sought to identify common genetic variant associations with prevalent AR and grass sensitization using existing genome-wide association study (GWAS) data and to determine whether genetic variants modify the protective effect of older siblings.

Method

Approximately 2.2 million genotyped or imputed single nucleotide polymorphisms were investigated in 4 large European adult cohorts for AR (3,933 self-reported cases vs 8,965 control subjects) and grass sensitization (2,315 cases vs 10,032 control subjects).

Results

Three loci reached genome-wide significance for either phenotype. The HLA variant rs7775228, which cis-regulates HLA-DRB4, was strongly associated with grass sensitization and weakly with AR (P_grass = 1.6 × 10⁻⁹; P_AR = 8.0 × 10⁻³). Variants in a locus near chromosome 11 open reading frame 30 (C11orf30) and leucine-rich repeat containing 32 (LRRC32), which was previously associated with atopic dermatitis and eczema, were also strongly associated with both phenotypes (rs2155219; P_grass = 9.4 × 10⁻⁹; P_AR = 3.8 × 10⁻⁸). The third genome-wide significant variant was rs17513503 (P_grass = 1.2 × 10⁻⁸; PAR = 7.4 × 10⁻⁷) which was located near transmembrane protein 232 (TMEM232) and solute carrier family 25, member 46 (SLC25A46). Twelve further loci with suggestive associations were also identified. Using a candidate gene approach, where we considered variants within 164 genes previously thought to be important, we found variants in 3 further genes that may be of interest: thymic stromal lymphopoietin (TSLP), Toll-like receptor 6 (TLR6) and nucleotide-binding oligomerization domain containing 1 (NOD1/CARD4). We found no evidence for variants that modified the effect of birth order on either phenotype.

Conclusions

This relatively large meta-analysis of GWASs identified few loci associated with AR and grass sensitization. No birth order interaction was identified in the current analyses.

Section snippets

Participants and studies

This analysis uses information collected from population samples of white adults taking part in 4 large epidemiologic projects: the British 1958 Birth Cohort (B58C)10, 13; the follow-up of the European Community Respiratory Health Survey (ECRHS2)14, 15, 16; the Northern Finland Birth Cohort of 1966 (NFBC1966)¹⁷; and the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA).18, 19 Participants provided information on AR, either underwent skin prick testing or had specific IgE levels

Results

Combining subjects with genome-wide data from the 4 studies, there were 3,933 cases of AR and 8,965 control subjects. Similarly, there were 2,315 subjects with IgE to grass sensitization and 10,032 control subjects. Table I shows the numbers of subjects and the case definitions used in each of the 4 studies.

Discussion

We believe that this is the first genome-wide association meta-analysis of AR and the largest genome-wide interaction study yet conducted for any allergic disease. We investigated the associations of prevalent AR and IgE levels to grass pollens for more than 2.2 million SNPs in almost 13,000 European white adults and also identified genes that might explain the protective effect of increasing birth order on disease. Although we identified several SNPs strongly associated with AR and IgE to

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: Details of the many charities, governmental bodies, and scientific funding organizations that supported the epidemiologic study, including phenotyping, DNA collection, and genotyping for the British 1958 Birth Cohort (B58C), the European Community Respiratory Health Survey (ECRHS2), the Northern Finland Birth Cohort of 1966 (NFBC1966), and the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA), can be found in this article’s Online Repository at www.jacionline.org. A. R. has received research support from the European Commission (through project GABRIEL, contract no. 018996 under the Integrated Program LSH-2004-1.2.5-1) and the Department of Health, United Kingdom. U. S. was supported by Medical Research Council studentship grant G0500539.

: Disclosure of potential conflict of interest: M. Wjst receives research support from the Helmholtz Center and EU Project European. T. Rochat receives research support from the Swiss National Foundation for Scientific Research. The rest of the authors have declared that they have no conflict of interest.

^∗: These authors contributed equally to this work.

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Rhinitis, sinusitis, and upper airway diseaseA genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order

Background

Objective

Method

Results

Conclusions

Section snippets

Participants and studies

Results

Discussion

Am J Hum Genet

Changes in asthma prevalence: two surveys 15 years apart

Arch Dis Child

Respiratory symptoms and atopy in Aberdeen schoolchildren: evidence from two surveys 25 years apart

BMJ

Discovering susceptibility genes for asthma and allergy

Nat Rev Immunol

Asthma genetics 2006: the long and winding road to gene discovery

Genes Immun

STAT6 as an asthma candidate gene: polymorphism-screening, association and haplotype analysis in a Caucasian sib-pair study

Hum Mol Genet

Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus

PLoS Genet

A large-scale, consortium-based genomewide association study of asthma

N Engl J Med

A genome-wide association study to identify genetic determinants of atopy in subjects from the United Kingdom

J Allergy Clin Immunol

Hay fever, hygiene, and household size

BMJ

Family size, infection and atopy: the first decade of the “hygiene hypothesis.”

Thorax

Does a higher number of siblings protect against the development of allergy and asthma? A review

J Epidemiol Community Health

Lifecourse influences on health among British adults: effects of region of residence in childhood and adulthood

Int J Epidemiol

The European Community Respiratory Health Survey

Eur Respir J

The association of family size with atopy and atopic disease

Clin Exp Allergy

Genes for asthma? An analysis of the European Community Respiratory Health Survey

Am J Respir Crit Care Med

Groups at risk in low birth weight infants and perinatal mortality

Acta Paediatr Scand

Reduced exposure to PM10 and attenuated age-related decline in lung function

N Engl J Med

Rhinitis, sinusitis, and upper airway disease
A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order