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This study aimed to investigate the effects of administration of xanthan gum-based fluid thickener on the regulation of postprandial blood glucose level, gene expression in the gastrointestinal tract, and gut microbiome. Six-week-old Sprague-Dawley rats were divided into two groups: with (Th group) and without (Co group) the administration of a xanthan gum-based fluid thickener for 5 wks. Blood glucose levels at 60 and 90 min after glucose administration were substantially decreased in the Th group. Glp1 and Glp1r expression in the ileum was significantly upregulated after continuous administration of thickener. RNA-seq analysis revealed that the cholesterol homeostasis, fatty acid metabolism, and glycolysis gene sets were enriched in the ileum of Th group. Microbial composition in the gut was altered after administrating the fluid thickener, and relative abundance in Erysipelotrichales and Christensenellaceae showed positive correlation with Glp1 and Glp1r expression in the ileum. Xanthan gum-based fluid thickener may ameliorate glucose/lipid metabolism.

Abstract ETS variant transcription factor 4 (ETV4) is a recently identified transcription factor that regulates gene expression-based biomarkers of asthma and IL6 production in an airway epithelial cell line. Given that ETV4 has not yet been implicated in asthma genetics, we performed genetic association studies of adult asthma in the ETV4 region using two independent Japanese cohorts (a total of 1532 controls and 783 cases). SNPs located between ETV4 and mesenchyme homeobox 1 (MEOX1) were significantly associated with adult asthma, including rs4792901 and rs2880540 (P = 5.63E−5 and 2.77E−5, respectively). The CC haplotype of these two SNPs was also significantly associated with adult asthma (P = 8.43E−7). Even when both SNPs were included in a logistic regression model, the association of either rs4792901 or rs2880540 remained significant (P = 0.013 or 0.007, respectively), suggesting that the two SNPs may have independent effects on the development of asthma. Both SNPs were expression quantitative trait loci, and the asthma risk alleles at both SNPs were correlated with increased levels of ETV4 mRNA expression. In addition, the asthma risk allele at rs4792901 was associated with increased serum IL6 levels (P = 0.041) in 651 healthy adults. Our findings imply that ETV4 is involved in the pathogenesis of asthma, possibly through the heightened production of IL6.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a complex lung disease caused by abnormal surfactant homeostasis. Here, the authors carry out a genome-wide association study of aPAP in a Japanese cohort, finding variants in the MHC and suggesting predisposition to abnormal antibody production.

Background: An orosomucoid-like 3 (ORMDL3)/gasdermin B (GSDMB) gene locus on chromosome 17q is consistently associated with childhood-onset asthma, which is highly atopic. As some evidence suggests the relationship between asthma and allergic sensitization reflects asthma patient susceptibility to augmented IgE responses driven by common environmental allergens rather than an increased asthma risk after allergen exposure, we aimed to determine any relationships between this locus region and childhood-onset adult asthma with regard to serum total IgE levels or allergic sensitization. Methods: We conducted a case–control association study using three independent Japanese populations (3869 total adults) and analyzed the ORs for association of rs7216389, an expression quantitative trait locus for ORMDL3/GSDMB, with adult asthma according to onset age. Additionally, associations between the rs7216389 genotype and total serum IgE levels or allergic sensitization was examined. Results: Rs7216389 was associated with both childhood-onset adult asthma (OR for asthmatic patients afflicted at the age of 10 years or younger = 1.61, p = 0.00021) and asthmatic patients with higher levels of total serum IgE (OR for asthmatic patients with IgE ≥1000IU/mL = 1.55, p = 0.0033). In both healthy controls and in the combined healthy and asthmatic individuals, rs7216389 was correlated with increased total serum IgE levels (p 0.1). Conclusions: ORMDL3/GSDMB is an important susceptibility gene for childhood-onset adult asthma in Japanese populations and this association is linked to elevated total serum IgE levels but not to allergic sensitization.

Preventing adverse pregnancy outcomes is crucial for maternal and child health. Periodontal disease is a risk factor for many systemic diseases including adverse pregnancy outcomes, such as preterm birth and low birth weight. In addition, the administration of the periodontopathic bacterium Porphyromonas gingivalis exacerbates obesity, glucose tolerance, and hepatic steatosis and alters endocrine function in the brown adipose tissue (BAT). However, the effects of having periodontal disease during pregnancy remain unclear. Thus, this study investigates the effect of P. gingivalis administration on obesity, liver, and BAT during pregnancy. Sonicated P. gingivalis (Pg) or saline (Co) was injected intravenously and administered orally to pregnant C57BL/6J mice three times per week. Maternal body weight and fetal body weight on embryonic day (ED) 18 were evaluated. Microarray analysis and qPCR in the liver and BAT and hepatic and plasma triglyceride quantification were performed on dams at ED 18. The body weight of Pg dams was heavier than that of Co dams; however, the fetal body weight was decreased in the offspring of Pg dams. Microarray analysis revealed 254 and 53 differentially expressed genes in the liver and BAT, respectively. Gene set enrichment analysis exhibited the downregulation of fatty acid metabolism gene set in the liver and estrogen response early/late gene sets in the BAT, whereas inflammatory response and IL6/JAK/STAT3 signaling gene sets were upregulated both in the liver and BAT. The downregulation of expression levels of Lpin1, Lpin2, and Lxra in the liver, which are associated with triglyceride synthesis, and a decreasing trend in hepatic triglyceride of Pg dams were observed. P. gingivalis administration may alter lipid metabolism in the liver. Overall, the intravenous and oral administration of sonicated P. gingivalis-induced obesity and modified gene expression in the liver and BAT in pregnant mice and caused fetuses to be underweight.

Abstract Background 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. 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. Methods This 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. Results In 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). Conclusions The 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.

Background: TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family and functions to limit type 2 immune responses implicated in allergic sensitization. Recent studies have shown that multiple intronic variants of TYRO3 were associated with asthma, implying that genetic variation could contribute to errant immune activation. We therefore hypothesized that expression quantitative trait loci (eQTLs) of the TYRO3 gene influence the development of allergic diseases (including asthma and allergic rhinitis) in Japanese populations. Methods: We performed a candidate gene case–control association study of 8 eQTLs of TYRO3 on atopy, asthma, and allergic rhinitis using 1168 unrelated Japanese adults who had GWAS genotyping. We then examined the genetic impact of rs2297377 (TYRO3) on atopy and allergic rhinitis in 2 other independent Japanese populations. Results: A meta-analysis of 3 Japanese populations (a total of 2403 Japanese adults) revealed that rs2297377 was associated with atopy and allergic rhinitis (OR = 1.29 and 1.31; P = 0.00041 and 0.0010, respectively). The risk allele at rs2297377 correlated with decreased expression of TYRO3 mRNA. The gene–gene interaction between HLA-DPB1 and TYRO3 was not significant with regard to sensitization. The estimated proportion of atopy and allergic rhinitis cases attributable to the risk genotype was 14% and 16%, respectively. Conclusions: Our study identified TYRO3 as an important susceptibility gene to atopy and allergic rhinitis in Japanese. Keywords: Allergic rhinitis, Asthma, Atopy, eQTL, TYRO3

Improvement of obesity is important for increasing longevity. The characteristics, size, and function of adipocytes are altered in patients with obesity. Adipose tissue is not only an energy storage but also an endocrine organ. Alteration of endocrine activities in adipose tissue, among them the functional decline of brown adipose tissue (BAT), is associated with obesity. Periodontal disease is a risk factor for systemic diseases since endotoxemia is caused by periodontal bacteria. However, the effect of periodontal disease on obesity remains unclear. Thus, this study aimed to investigate the effect of endotoxemia due to Porphyromonas gingivalis, a prominent cause of periodontal disease, on the BAT. Herein, endotoxemia was induced in 12-week-old C57BL/6J mice through intravenous injection of sonicated 108 CFU of P. gingivalis (Pg) or saline (control [Co]) once. Eighteen hours later, despite no inflammatory M1 macrophage infiltration, inflammation-related genes were upregulated exclusively in the BAT of Pg mice compared with Co mice. Although no marked histological changes were observed in adipose tissues, expressions of genes related to lipolysis, Lipe and Pnpla2 were downregulated after P. gingivalis injection in BAT. Furthermore, expression of Pparg and Adipoq was downregulated only in the BAT but not in the white adipose tissues, along with downregulation of Ucp1 and Cidea expression, which are BAT-specific markers, in Pg mice. Microarray analysis of the BAT showed 106 differentially expressed genes between Co and Pg mice. Gene set enrichment analysis revealed that the cholesterol homeostasis gene set and PI3/Akt/mTOR signaling gene set in BAT were downregulated, whereas the TGF-β signaling gene set was enriched in Pg mice. Overall, intravenous injection of sonicated P. gingivalis altered the endocrine functions of the BAT in mice. This study indicates that endotoxemia by P. gingivalis potentially affects obesity by disrupting BAT function.

Several reports have shown that the photo-bio-modulation of cells by various lasers has favorable biological effects. However, the effects of low-level Er:YAG laser irradiation on osteoblasts remain unclear. The purpose of this study was to evaluate the effects of low-level Er:YAG laser irradiation on proliferation and osteogenic differentiation of primary osteoblast-like cells isolated from the calvariae of 3–5-day-old Wistar rats. Cells were irradiated by Er:YAG laser at energy fluences of 2.2, 3.3, and 4.3 J/cm2, respectively. After irradiation, cell surface temperatures were measured and cell proliferation was evaluated by flow cytometry and CCK-8. Calcification was evaluated by measuring areas of Alizarin red S staining after 7, 14, and 21 days culture in osteoinductive medium. Gene expression in non-irradiated and laser-irradiated cells was evaluated by qPCR at 3, 6, and 12 h, as well as 1, 3, 7, and 14 days after irradiation. Microarray analysis was performed to comprehensively evaluate the gene expression of non-irradiated and irradiated cells at 3.3 J/cm2 at 6 h after irradiation. No pronounced increase of cell surface temperature was induced by irradiation. Irradiation did not affect osteoblast-like cell proliferation. Osteoblast-like cell calcification was significantly increased 7 days after Er:YAG laser irradiation at 3.3 J/cm2. Bglap expression was significantly increased in cells irradiated at 3.3 J/cm2 6 h post-irradiation. Microarray analysis showed that irradiation at 3.3 J/cm2 caused an upregulation of inflammation-related genes and downregulation of Wisp2. Gene set enrichment analysis also clarified enrichment of inflammation-related and Notch signaling gene sets. In conclusion, low-level Er:YAG laser irradiation at 3.3 J/cm2 enhanced calcification of primary osteoblast-like cells via enhanced Bglap expression and enriched Notch signaling.

Background: Recent studies have demonstrated that a coding SNP (rs6967330, Cys529→Tyr) in cadherin-related family member 3 (CDHR3), which was previously associated with wheezing illness and hospitalizations in infancy, could support efficient human rhinovirus C (RV-C) entry and replication. Here, we sought to examine the genetic contribution of this variant to the development of adult asthma. Methods: We performed a candidate gene case–control association study of 2 independent Japanese populations (a total of 3366 adults). The odds ratios (ORs) for association of the A allele at rs6967330 with adult asthma were calculated according to age at onset of asthma. In addition, the effect of the CDHR3 genotype on the development of specific asthma phenotypes was examined. Results: The A allele was associated with asthma (OR = 1.56; Mantel–Haenszel p = 0.0040) when the analysis was limited to patients with early-onset adult asthma. In addition, when the analysis was limited to atopic individuals, a stronger association of the CDHR3 variant with early-onset asthma was found, and interaction of the CDHR3 genotype with atopy was demonstrated. Finally, a significant association of this variant was specifically found with a phenotype of asthma characterized by atopy, early-onset, and lower lung function. Conclusions: Our study supports the concept that the CDHR3 variant is an important susceptibility factor for severe adult asthma in individuals who develop the disease in early life. The interaction between the CDHR3 variant and atopy indicates that genetic predisposition to early respiratory viral infection is combined with atopy in promoting asthma.

Many risk factors related to the development of non-alcoholic fatty liver disease (NAFLD) have been proposed, including the most well-known of diabetes and obesity as well as periodontitis. As periodontal pathogenic bacteria produce endotoxins, periodontal treatment can result in endotoxemia. The aim of this study was to investigate the effects of intravenous, sonicated Porphyromonas gingivalis (Pg) injection on glucose/lipid metabolism, liver steatosis, and gut microbiota in mice. Endotoxemia was induced in C57BL/6J mice (8 weeks old) by intravenous injection of sonicated Pg; Pg was deactivated but its endotoxin remained. The mice were fed a high-fat diet and administered sonicated Pg (HFPg) or saline (HFco) injections for 12 weeks. Liver steatosis, glucose metabolism, and gene expression in the liver were evaluated. 16S rRNA gene sequencing with metagenome prediction was performed on the gut microbiota. Compared to HFco mice, HFPg mice exhibited impaired glucose tolerance and insulin resistance along with increased liver steatosis. Liver microarray analysis demonstrated that 1278 genes were differentially expressed between HFco and HFPg mice. Gene set enrichment analysis showed that fatty acid metabolism, hypoxia, and TNFα signaling via NFκB gene sets were enriched in HFPg mice. Although sonicated Pg did not directly reach the gut, it changed the gut microbiota and decreased bacterial diversity in HFPg mice. Metagenome prediction in the gut microbiota showed enriched citrate cycle and carbon fixation pathways in prokaryotes. Overall, intravenous injection of sonicated Pg caused impaired glucose tolerance, insulin resistance, and liver steatosis in mice fed high-fat diets. Thus, blood infusion of Pg contributes to NAFLD and alters the gut microbiota.

Background:: Chronic rhinosinusitis (CRS), which is clinically classified into CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP), shows considerable geographic differences and heterogeneity. Eosinophilic (E) CRS with nasal polyps (ECRSwNP) has a higher degree of disease severity and higher frequency of comorbid asthma. Epidemiologic studies in different ethnic populations have improved understanding of the pathophysiology of the disease. Here we report the clinical characteristics of Japanese patients with medically refractory CRS undergoing endoscopic sinus surgery (ESS). Methods:: We recruited a total of 210 CRS patients and assessed them by nasal endoscopy, the Lund-Mackay score using computed tomography (CT), peripheral eosinophilia and smoking status. We also examined the comorbidity of asthma, effects of age and lung functions in the patients. Results:: In this study, 13% of CRSwNP patients and 20% of CRSwNP patients with peripheral blood eosinophilia exhibited obstructive lung dysfunction (FEV1/FVC

Allergic diseases are complex diseases caused by a combination of genetic and environmental factors. To determine the genetic components of these diseases and to discover the genes and cellular pathways underlying them, a large number of genetic studies have been conducted. Progress in genetics enables us to conduct genome-wide association studies (GWASs), which is a comprehensive and unbiased approach to identify susceptibility loci for multifactorial diseases. Recent GWASs have convincingly detected a large number of loci associated with allergic diseases. Candidate genes in the susceptibility loci suggest roles for epithelial barrier functions, innate-adaptive immunity, IL-1 family signaling, regulatory T cells and the vitamin D pathway in the pathogenesis of allergic diseases. Interestingly, the IL1RL1, HLA, IL13 and C11orf30 regions are overlapping susceptibility loci among atopic dermatitis and asthma or allergic rhinitis. Although a more complete collection of associated genes and pathways is needed, biologic insights revealed by GWASs improve our understanding of the pathophysiology of human allergic diseases and contribute to the development of better treatment and preventive strategies.

Background: Atopy is a phenotypically heterogeneous condition, and the extent to which atopy accounts for asthma is controversial. In this study, we aimed to identify the presence of distinct sensitization patterns to common inhaled allergens and their association with asthma, allergic rhinitis and TSLP genotypes. Methods: We studied 1683 adults from Tsukuba, a city in central Japan and 297 adults from Kamishihoro, a cedar-free, birch-dominant town in northern Japan. Levels of total serum IgE and specific IgE antibodies towards 14 major inhaled allergens were measured. With the use of these measures, cluster analysis was applied to classify the subjects' sensitization patterns. We also examined the genetic effects of 2 TSLP functional SNPs on the development of each sensitization pattern. Results: In the Tsukuba study, cluster analysis identified four clusters, including "Dust mite dominant", "Multiple pollen", "Cedar dominant", and "Low reactivity". In the Kamishihoro study, "Dust mite dominant", "Multiple pollen" and "Low reactivity" clusters were also identified, but a "Cedar dominant" cluster was not formed. The association with asthma was strongest for the "Dust mite dominant" cluster in both the Tsukuba and the Kamishihoro studies. In never smokers, both SNPs were associated with the "Dust mite dominant" cluster (OR > 1.2). In contrast, in current or past smokers, these alleles were inversely associated with the "Multiple pollen" cluster (OR

Although our previous GWAS failed to identify SNPs associated with pulmonary function at the level of genomewide significance, it did show that the heritability for FEV1/FVC was 41.6% in a Japanese population, suggesting that the heritability of pulmonary function traits can be explained by the additive effects of multiple common SNPs. In addition, our previous study indicated that pulmonary function genes identified in previous GWASs in non-Japanese populations accounted for 4.3% to 12.0% of the entire estimated heritability of FEV1/FVC in a Japanese population. Therefore, given that many loci with individual weak effects may contribute to asthma risk, in this study, we created a quantitative score of genetic load based on 16 SNPs implicated in lower lung function in both Japanese and non-Japanese populations. This genetic risk score (GRS) for lower FEV1/FVC was consistently associated with the onset of asthma (P = 9.6 × 10(-4)) in 2 independent Japanese populations as well as with the onset of COPD (P = 0.042). Clustering of asthma patients based on GRS levels indicated that an increased GRS may be responsible for the development of a particular phenotype of asthma characterized by early onset, atopy, and severer airflow obstruction.

Bronchial asthma is a common inflammatory disease caused by a combination of genetic and environmental factors. To discover the genes and cellular pathways underlying asthma, a large number of genetic studies have been conducted. Genome-wide association studies (GWAS), which comprehensively assess genes related to multifactorial diseases and drug reactivity, have enhanced understanding of human diseases. From 2007, GWAS of susceptibility to asthma in Caucasian, Mexican, and African-ancestry populations have been conducted and several susceptible loci were identified. Recently, much larger consortium-based GWAS analyses of collaborative samples with adequate statistical power were performed, and the implicated genes suggested a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Furthermore, GWAS identified candidate loci associated with natural variations in lung function, blood eosinophilia and eosinophilic esophagitis, which is inflammation of the esophagus with abnormal infiltration of eosinophils in an allergic reaction. Comparing GWAS in asthma and these clinical phenotypes might help to clarify the mechanisms underlying asthma. Pharmacogenomics analyses using GWAS regarding genetic factors related to the effectiveness of inhaled corticosteroid (ICS) therapy and inhaled beta2-adrenergic agonists are ongoing now. Although a more complete collection of associated genes and pathways is needed, biologic insights revealed by GWAS provide valuable insights into the pathophysiology of asthma and contribute to the development of better treatment and preventive strategies.

Most of the previously reported loci for total immunoglobulin E (IgE) levels are related to Th2 cell-dependent pathways. We undertook a genome-wide association study (GWAS) to identify genetic loci responsible for IgE regulation. A total of 479,940 single nucleotide polymorphisms (SNPs) were tested for association with total serum IgE levels in 1180 Japanese adults. Fine-mapping with SNP imputation demonstrated 6 candidate regions: the PYHIN1/IFI16, MHC classes I and II, LEMD2, GRAMD1B, and chr13∶60576338 regions. Replication of these candidate loci in each region was assessed in 2 independent Japanese cohorts (n = 1110 and 1364, respectively). SNP rs3130941 in the HLA-C region was consistently associated with total IgE levels in 3 independent populations, and the meta-analysis yielded genome-wide significance (P = 1.07×10(-10)). Using our GWAS results, we also assessed the reproducibility of previously reported gene associations with total IgE levels. Nine of 32 candidate genes identified by a literature search were associated with total IgE levels after correction for multiple testing. Our findings demonstrate that SNPs in the HLA-C region are strongly associated with total serum IgE levels in the Japanese population and that some of the previously reported genetic associations are replicated across ethnic groups.

Smoking is a major public health problem, but the genetic factors associated with smoking behaviors are not fully elucidated. Here, we have conducted an integrated genome-wide association study to identify common copy number polymorphisms (CNPs) and single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) in Japanese smokers (N = 17,158). Our analysis identified a common CNP with a strong effect on CPD (rs8102683; P=3.8 x 10(-42)) in the 19q13 region, encompassing the CYP2A6 locus. After adjustment for the associated CNP, we found an additional associated SNP (rs11878604; P=9.7 x 10(-30)) located 30 kb downstream of the CYP2A6 gene. Imputation of the CYP2A6 locus revealed that haplotypes underlying the CNP and the SNP corresponded to classical, functional alleles of CYP2A6 gene that regulate nicotine metabolism and explained 2% of the phenotypic variance of CPD (ANOVA F-test P=9.5 x 10(-52)). These haplotypes were also associated with smoking-related diseases, including lung cancer, chronic obstructive pulmonary disease and arteriosclerosis obliterans.

Atopic dermatitis is a chronic inflammatory skin disease. Multiple genetic and environmental factors are thought to be responsible for susceptibility to AD. In this study, we collected 2,478 DNA samples including 209 AD patients and 729 control subjects from Taiwanese population and 513 AD patients and 1027 control subject from Japanese population for sequencing and genotyping ORAI1. A total of 14 genetic variants including 3 novel single-nucleotide polymorphisms (SNPs) in the ORAI1 gene were identified. Our results indicated that a non-synonymous SNP (rs3741596, Ser218Gly) associated with the susceptibility of AD in the Japanese population but not in the Taiwanese population. However, there is another SNP of ORAI1 (rs3741595) associated with the risk of AD in the Taiwanese population but not in the Japanese population. Taken together, our results indicated that genetic polymorphisms of ORAI1 are very likely to be involved in the susceptibility of AD.

Asthma is a complex phenotype influenced by genetic and environmental factors. We conducted a genome-wide association study (GWAS) with 938 Japanese pediatric asthma patients and 2,376 controls. Single-nucleotide polymorphisms (SNPs) showing strong associations (P

White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P

Atopic dermatitis (AD) is a common inflammatory skin disease caused by multiple genetic and environmental factors. AD is characterized by the local infiltration of T helper type 2 (Th2) cells. Recent clinical studies have shown important roles of the Th2 chemokines, CCL22 and CCL17 in the pathogenesis of AD. To investigate whether polymorphisms of the CCL22 gene affect the susceptibility to AD, we conducted association studies and functional studies of the related variants. We first resequenced the CCL22 gene and found a total of 39 SNPs. We selected seven tag SNPs in the CCL22 gene, and conducted association studies using two independent Japanese populations (1(st) population, 916 cases and 1,032 controls; 2(nd) population 1,034 cases and 1,004 controls). After the association results were combined by inverse variance method, we observed a significant association at rs4359426 (meta-analysis, combined P = 9.6×10⁻⁶; OR, 0.74; 95% CI, 0.65-0.85). Functional analysis revealed that the risk allele of rs4359426 contributed to higher expression levels of CCL22 mRNA. We further examined the allelic differences in the binding of nuclear proteins by electrophoretic mobility shift assay. The signal intensity of the DNA-protein complex derived from the G allele of rs223821, which was in absolute LD with rs4359426, was higher than that from the A allele. Although further functional analyses are needed, it is likely that related variants play a role in susceptibility to AD in a gain-of-function manner. Our findings provide a new insight into the etiology and pathogenesis of AD.