Gene polymorphisms associated with allergic sensitization revealed by the University of Tsukuba and the Jikei University School of Medicine

A research group led by Professor Emiko Noguchi of the Department of Medical Genetics, Institute of Medicine at the University of Tsukuba, and Associate Professor Tomomitsu Hirota of the Division of Molecular Genetics, Research Center for Medical Science, the Jikei University School of Medicine, has discovered gene regions (gene polymorphisms) associated with allergic sensitization through a large-scale genome analysis in Japanese and Caucasian populations. This study clarified sensitization-associated gene polymorphisms found in the Japanese population and those shared by both populations and also identified gene polymorphisms associated with polysensitization for the first time. The findings are considered an important step toward understanding molecular mechanisms pertinent to allergic diseases. The study was published in the Journal of Allergy and Clinical Immunology.

The research group conducted a genome-wide association study using information on gene polymorphisms and diseases in a general population of 46,602 Japanese people collected by the University of Tsukuba and Tohoku Medical Megabank Organization. As a result, 18 allergic sensitization-associated gene polymorphisms were detected, including two novel polymorphisms not reported previously. Moreover, they performed a meta-analysis of the results of a genome-wide association study in 25,032 Caucasian subjects and the results of the association study in Japanese subjects and detected 23 allergic sensitization-associated gene polymorphisms, including four novel ones.

They also performed a genome-wide association study for polysensitization, which is sensitization to multiple different allergens. Eight gene polymorphisms associated with polysensitization were identified. Polysensitization is "IgE reactivity to multiple unrelated (or apparently unrelated) allergenic substances" and has been suggested to be associated with refractory allergic diseases. The eQTL analysis on the effects of the identified disease susceptibility gene polymorphisms on gene expression showed that the risk-associated T allele of rs61566046 on chromosome 11, one of the polysensitization-associated polymorphisms, was associated with decreased expression of the LRRC32 gene. As LRRC32 encodes the glycoprotein GARP, the decreased LRRC32 expression was considered to interfere with regulatory T cell function, resulting in increased susceptibility to polysensitization. They also found that the risk-associated T allele of the gene polymorphism rs3769684 on chromosome 2 was associated with increased CD28 expression in CD4-positive T cells. Moreover, the risk-associated G allele of the gene polymorphism rs6790260 on chromosome 3 was associated with increased expression of the protein LPP in B cells and dendritic cells.

Linkage disequilibrium score regression (LDSC) analysis using these genotyping results revealed strong positive genetic correlations of allergic sensitization with asthma, allergic rhinitis, and pollinosis, while no such correlation was found with atopic dermatitis.

Two hypotheses have been proposed for the pathogenesis of atopic dermatitis. One hypothesizes that primary immune dysfunction leads to IgE antibody production, resulting in epithelial barrier damage and local skin inflammation. The other holds that skin dysfunction itself is the origin of atopic dermatitis and considers immunological dysfunction a secondary phenomenon. The results of the present study support the latter hypothesis, providing the gene polymorphism analysis data revealing that "genetic predisposition to allergic sensitization contributes less to the development of atopic dermatitis than to asthma, allergic rhinitis, and pollinosis." As the relationships between allergic sensitization and genotypes in specific gene regions were defined more precisely in this study, candidate gene regions that are important for understanding the molecular mechanisms pertinent to allergic diseases have been narrowed down. It is hoped that studies on these genes will reveal a new molecular basis for allergic diseases and contribute to developing preventive and therapeutic approaches to allergic diseases.

Journal Information
Publication: Journal of Allergy and Clinical Immunology
Title: A genome-wide meta-analysis reveals shared and population-specific variants for allergic sensitization
DOI: 10.1016/j.jaci.2024.11.033