Genetic loci for lung function in Japanese adults with adjustment for exhaled nitric oxide levels as airway inflammation indicator

Mitsuhiro Yamada,Eiichi N Kodama,Nobuo Fuse,Kazuyuki Kojima ,Miyuki Sakurai,Ikuko N Motoike,Takashi Ohe,Naoya Fujino,Shu Tadaka,Hiroaki Sugiura ,Ayumi Mitsune,Tomohiro Ichikawa,Atsushi Hozawa,Soichi Ogishima,Masakazu Ichinose,Shinichi Kuriyama,Tomohiro Nakamura,Kengo Kinoshita,Junichi Sugawara,Akira Uruno,Fumiki Katsuoka,Kichiya Suzuki,Matsuyuki Shirota,Yohei Hamanaka,Tadahisa Numakura,Masayuki Yamamoto

doi:10.1038/s42003-021-02813-8

Mitsuhiro Yamada, Eiichi N Kodama + Show 24 more

Open Access

https://doi.org/10.1038/s42003-021-02813-8

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Abstract

Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases. Because type 2 airway inflammation influences lung function, genome wide association studies (GWAS) for lung function would be improved by adjustment with an indicator of the inflammation. Here, we performed a GWAS for lung function with adjustment for exhaled nitric oxide (FeNO) levels in two independent Japanese populations. Our GWAS with genotype imputations revealed that the RNF5/AGER locus including AGER rs2070600 SNP, which introduces a G82S substitution of AGER, was the most significantly associated with FEV1/FVC. Three other rare missense variants of AGER were further identified. We also found genetic loci with three candidate genes (NOS2, SPSB2 and RIPOR2) associated with FeNO levels. Analyses with the BioBank-Japan GWAS resource revealed genetic links of FeNO and asthma-related traits, and existence of common genetic background for allergic diseases and their biomarkers. Our study identified the genetic locus most strongly associated with airway obstruction in the Japanese population and three genetic loci associated with FeNO, an indicator of type 2 airway inflammation in adults.

Highlights

Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases
Because FeNO is the biomarker for type 2 airway inflammation and the measurement of FeNO is widely used for a diagnosis of asthma, we examined the genetic correlation between FeNO and asthma using linkage disequilibrium (LD) score regression (LDSC)
The 3D structure-based assessment suggests that the SNP in advanced glycosylation end product-specific receptor (AGER) introduces a G82S substitution into one of the immunoglobulin domains in AGER, which likely affects the molecular function of the receptor

Summary

Introduction

Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases. Frequencies of exacerbation in Japanese and Korean COPD populations are smaller than those in the US and Europe COPD populations[24,26,28] Based on these reasons, we decided to explore genetic variants associated with the lung function measures in the Japanese population, as it could provide meaningful information for elucidating the genetic vulnerability for pulmonary diseases including COPD in the world. The TMM Project aims to establish an integrated biobank, sharing both biological samples and genomeomics information along with routine health examination data[33,34] To this end, we have been conducting a large-scale ethnic-specific SNP array analysis[32], through which we are attempting to elucidate the genetic vulnerabilities of common diseases including COPD to enable personalized health care[32]. Our GWAS for FeNO is the largest one for adults in terms of the number of subjects

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Conclusion