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. 2023 Feb 20;2(2):100086.
doi: 10.1016/j.jacig.2023.100086. eCollection 2023 May.

A genome-wide association study for allergen component sensitizations identifies allergen component-specific and allergen protein group-specific associations

Wataru Morii  1 , Koki Kasai  1 , Takako Nakamura  1 , Daisuke Hayashi  1 , Monami Hara  1 , Tatsuhiko Naito  2   3   4 , Kyuto Sonehara  2   5 , Tatsuki Fukuie  6 , Mayako Saito-Abe  6 , Limin Yang  6 , Kiwako Yamamoto-Hanada  6 , Masami Narita  6   7 , Kazushi Maruo  8 , Yukinori Okada  2   4   5   9   10 , Emiko Noguchi  1 , Yukihiro Ohya  6
Affiliations

A genome-wide association study for allergen component sensitizations identifies allergen component-specific and allergen protein group-specific associations

Wataru Morii et al. J Allergy Clin Immunol Glob. .

Abstract

Background: Allergic diseases are some of the most common diseases worldwide. Genome-wide association studies (GWASs) have been conducted to elucidate the genetic factors of allergic diseases. However, no GWASs for allergen component sensitization have been performed.

Objective: We sought to detect genetic variants associated with differences in immune responsiveness against allergen components.

Methods: The participants of the present study were recruited from the Tokyo Children's Health, Illness, and Development study, and allergen component-specific IgE level at age 9 years was measured by means of allergen microarray immunoassays. We performed GWASs for allergen component sensitization against each allergen (single allergen component sensitization, number of allergen components analyzed, n = 31), as well as against allergen protein families (allergen protein group sensitization, number of protein groups analyzed, n = 16).

Results: We performed GWAS on 564 participants of the Tokyo Children's Health, Illness, and Development study and found associations between Amb a 1 sensitization and the immunoglobulin heavy-chain variable gene on chromosome 14 and between Phl p 1 sensitization and the HLA class II region on chromosome 6 (P < 5.0 × 10-8). A GWAS-significant association was also observed between the HLA class II region and profilin sensitization (P < 5.0 × 10-8).

Conclusions: Our data provide the first demonstration of genetic risk for allergen component sensitization and show that this genetic risk is related to immune response genes including immunoglobulin heavy-chain variable gene and HLA.

Keywords: Genome-wide association study; HLA; IGHV; allergen components; immunogenetics.

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Figures

Fig 1
Fig 1
Flow chart of the present study.
Fig 2
Fig 2
3-Dimensional Manhattan plots of GWAS against allergen components and protein group sensitization. The x-axis (chromosome) represents the genomic locations; the y-axis, the phenotypes (ie, allergen component/allergen protein group sensitizations); and the z-axis (-log10(P)), the -log10 (P values).
Fig 3
Fig 3
GWAS for sensitization against Amb a 1. A, Manhattan plot for GWAS with sensitization against Amb a 1. The x-axis indicates chromosomal positions, and the y-axis, the −log10 (P values) calculated with SAIGE. The red line indicates the genome-wide significance level (P = 5.0 × 10−8), and the blue line, the genome-wide suggestive level (P = 1.0 × 10−5). B, Quantile-quantile (Q-Q) plot of GWAS with sensitization against Amb a 1. The Q-Q plot indicates the expected −log10 (P values) vs the observed −log10 (P values). C, Regional association plots of the GWAS-significant region on chromosome 14. Variants are colored according to their linkage disequilibrium (LD) based on the 1000 Genomes Project Phase 3’s EAS reference panel, and the top-associated SNP (rs35735004) is marked with a purple diamond. D, Regional association plots of the GWAS-significant region on chromosome 14 after conditioning on the top-associated SNP (rs35735004).
Fig 4
Fig 4
GWAS for sensitization against Phl p 1. A, Manhattan plot for GWAS with sensitization against Phl p 1. B, Association results of HLA class II alleles. The x-axis shows the HLA alleles, and the y-axis, the −log10 (P values). The red line indicates the genome-wide significance level (P = 5.0 × 10−8), and the blue line, the suggestive level (P = 1.0 × 10−5). C, Association results of 4-digit HLA class II alleles. Each circle point shows the −log10 (P values) for the 4-digit HLA class II alleles. The red line indicates the genome-wide significance level (P = 5.0 × 10−8), and the blue line, the genome-wide suggestive level (P = 1.0 × 10−5). D, Association results of HLA class II amino-acid polymorphisms. Each circle point shows the −log10 (P values) for each amino-acid polymorphism. The x-axis indicates the amino-acid positions. The red line indicates the genome-wide significance level (P = 5.0 × 10−8), and the blue line, the genome-wide suggestive level (P = 1.0 × 10−5).
Fig 5
Fig 5
GWAS for sensitization against profilin. A, Manhattan plot for GWAS with sensitization against profilin. B, Association results of HLA class II alleles. The x-axis shows the HLA alleles, and the y-axis, the −log10 (P values). The red line indicates the genome-wide significance level (P = 5.0 × 10−8), and the blue line, the genome-wide suggestive level (P = 1.0 × 10−5). C, Association results of 4-digit HLA class II alleles. Each circle point shows the −log10 (P values) for the 4-digit HLA class II alleles. The red line indicates the genome-wide significance level (5.0 × 10−8), and the blue line, the genome-wide suggestive level (1.0 × 10−5). D, Association results of HLA class II amino-acid polymorphisms. Each circle point shows the −log10 (P values) for each amino-acid polymorphism. The x-axis indicates the amino-acid positions. The red line indicates the genome-wide significance level (5.0 × 10−8), and the blue line, the genome-wide suggestive level (1.0 × 10−5).
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