A cis-eQTL allele regulating reduced expression of CHI3L1 is associated with late-onset adult asthma in Japanese cohorts

Jun Kanazawa,Yohei Yatagai,Masaharu Nishimura,Satoshi Konno,Tohru Sakamoto,Nobuyuki Hizawa,Haruna Kitazawa,Takashi Naito,Mayumi Tamari,Takefumi Saito,Yoshiko Kaneko,Hiroaki Iijima,Tomomitsu Hirota,Emiko Noguchi,Hironori Masuko

doi:10.1186/s12881-019-0786-y

Abstract

BackgroundThe chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes.MethodsThis case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters.ResultsIn the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07–1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03–1.61; P = 0.027).ConclusionsThe genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.

Highlights

The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome
Search for chitinase 3-like 1 (CHI3L1) eQTLs for a genetic association study We identified 34 single-nucleotide polymorphism (SNP) associated with expression levels of CHI3L1 mRNA in the lung, six of which had previously been genotyped in the Tsukuba discovery genome-wide association study (GWAS) cohort (Table 1; Fig. 1)
Among the six eQTLs, the presence of the C allele at rs946261, which was significantly associated with reduced expression of CHI3L1 mRNA in the lung (P = 8.30E-09), was associated with the development of asthma

Summary

Introduction

The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. YKL-40 is expressed by multiple cell types in the lung, such as macrophages, neutrophils, and epithelial cells [1, 2]. This protein was increased in the serum from patients with community-acquired pneumonia severe enough to necessitate hospitalization [3]. We hypothesized that altered expression of YKL-40 may result in inappropriate inflammasome activation, and may play an important role in chronic pulmonary diseases such as asthma

Methods

Results

Discussion

Conclusion